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Handbook of Vitamins

Janos Zempleni, John W. Suttie, Jesse F. Gregory III, Patrick J. Stover

3 Vitamin K

Publication details https://www.routledgehandbooks.com/doi/10.1201/b15413-4 Janos Zempleni, John W. Suttie, Jesse F. Gregory III, Patrick J. Stover, John W. Suttie Published online on: 29 Jul 2013

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Efficacy and Hazards of Pharmacological Doses of Vitamin K Doses of Vitamin of Pharmacological andHazards Efficacy 3.8.2 3.8.1 KRequirements Vitamin 3.7.7 3.7.6 3.7.5 3.7.4 3.7.3 3.7.2 3.7.1 KStatus Vitamin of Altered Impacts Health 3.6.3 3.6.2 3.6.1 Biochemical Role K of Vitamin 3.5.3 3.5.2 3.5.1 K–Dependent Proteins Vitamin 3.4.5 3.4.4 3.4.3 3.4.2 3.4.1 Metabolism KContent of Food Vitamin and Procedures Analytical 3.2.4 3.2.3 3.2.2 3.2.1 Chemistry History 3

...... 3.2.3.3 3.2.3.2 3.2.3.1 Humans Animals K Status FactorsVitamin Influencing Other Possible Role Vascular in Calcification Possible Role Bone in Health Newborn of the Disease Hemorrhagic Therapy Anticoagulant KDeficiencyAdult Vitamin Methodology KEpoxide Reductase Vitamin The K–Dependent Carboxylase Vitamin The Discovery of γ K–Dependent Proteins Vitamin Other Proteins TissueCalcified Factors Plasma Clotting K of Vitamin Degradation Metabolic Synthesis of MK-4 K Tissue of Distribution Vitamin K ofPlasma Concentrations Vitamin K of Vitamin Transport and Absorption Properties Physical Chemical and Antagonists and Forms, of Commercial Analogs, Structures Nomenclature and Structure Isolation ...... John W. Suttie Vitamin K ...... 90 ...... 96

...... 112 ...... 111 ...... Action of Vitamin Antagonists K of Form Vitamin Commercial Biological Their and Analogs Activity ...... 90 ...... 107 ...... -Carboxyglutamic Acid -Carboxyglutamic ...... 111 ...... 99 ...... 108 ...... 100 ...... 100 ...... 103 ...... 102 ...... 108 ...... 90 ...... 109 ...... 98 ...... 94 ...... 106 ...... 107 ...... 99 ...... 97 ...... 109 ...... 103 ...... 103 ...... 110 ...... 104 ...... 96 ...... 92 ...... 91 ...... 110 ...... 91 ...... 94 ...... 113 ...... 91 ...... 113 90 89 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 The compound first isolated from putrefied fish meal and called at that time vitamin K vitamin time that at called and meal fish putrefied from isolated phytonadione.first compound is The phylloquinone for nomenclature (USP) Pharmacopeia States United The none. tory of the discovery of vitamin K has been reviewed been K has by [7,8] them discovery of of the vitamin tory [9–11]. by and others Nobel in PhysiologyPrize and Medicine was awarded to Dam and Doisy, and much of the early his- Sources of this form of the vitamin, such as putrefied fish meal, contained a number of different K ofthe of vitamins number a contained meal, fish putrefied as such vitamin, the of form this of Sources as a yellow oil. Subsequent studies soon established that the active principle was a quinone and and quinone a K vitamin was principle active the that established soon studies Subsequent oil. yellow a as alfalfa from vitamin isolation ofthe the in Universityresulted ofthe of Zurich Karrer with oration word koagulation German the of letter first the also was it but time, that at activity vitamin postulated or existing an describe to fat-solublenew a was chick which K. Not he vitamin, vitamin called only wasthe K the first letter ofofthealphabet that was not used vitamin antihemorrhagic the that [4,5] proposed 1935 in sources and animal and vegetable in component active the study to continued Dam vitamins. known the of any of administration the by cured be not could disease This source. protein a as yeast and meal fish fed chicks in hemorrhages and external internal or meal, meat or fish ether-extracted fed were chicks when seen defects clotting [3]described Halbrook and Holst[2] and al. et McFarlane slowly. clotted animals these Subsequently, from taken blood that developedrolsand hemorrhages ste- solventsremove nonpolar to the with extracted been had that diets ingesting chicks that noted Dam who was investigating the possible essential role of cholesterol in the diet of the chick. Dam [1] 1930s early the in by conducted of Henrik experiments aseries Kwas discovered through Vitamin 3.1 90 is produced in green plants and is generally called vitamin K vitamin called generally is and plants green in produced is 2-methyl-3-phytyl-1,4-naphthoquinone compound The diet. K–deficient vitamin a fed animals in activity antihemorrhagic an exhibit that compound this ofderivatives all and 1,4-naphthoquinone on Nomenclature of[13]. Quinones term The report subcommittee Biochemistry of Union Chemistry–International Applied and Pure of Union The nomenclature in general use at the present time is that of the most recently adopted International s 3.2.2 Section 3.3. in described procedures the by be separated can lipid, forms various ofthe muchfrom fraction vitamin the of contaminated the ofK contentthe vitamin of foods noware available, and following K ofseparation vitamin the total have K foodvarious from tionmatrices developed ofbeen vitamin [12]. extensive Rather databases Methods for between water efficientthe vitamin. and partitioned hexane crude the to obtain extrac- quantities)samples (kilogram of tissues can be extracted with acetone alone, extract and this can be Large ether. or hexane followedby acetone with it extracting then and sulfate sodium anhydrous with tissue wet the grinding first by or chloroform–methanol, as such conditions, dehydrating of product desired extractions extracts. usually in made are the with Initial initial the use of some type of amount small the byalways is complicated biologicalmaterial from K vitamin isolationof The 3.2.1 3.2 called vitamin K called vitamin compound, fish This product. putrefied crystalline from a was alfalfa vitamin from isolated oil the the to ofcontrast in which form meal, a isolated also group Doisy The [6]. Louis St. in group Numerous groups were involved and newDam’sthis vitamin, in to attempts characterize collab-

History C h I solat 1 tructure emistry was characterized as 2-methyl-3-phytyl-1,4-naphthoquinonewas characterized and bysynthesized Doisy’s i on 2 , contained an unsaturated , side an contained unsaturated chain at the 3-position of the naphthoquinone ring. 2 series with differing chain length polyprenyl groups at the 3-position. The 1943 3-position. polyprenyl The the length at groups chain differing with series

and N omenclature . vitamin K is a as ofused generic descriptor vitamin 2-methyl- 1 , but is preferably called phylloqui- preferablycalled is but , Handbook of Vitamins Handbook 2 is one of one is Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 phylloquinone by apathway not yet clearly defined Section (see 3.4.4). bacterial minor product but can be a byformed by the ofalkylation animals menadione is or the degradation ofthrough (MK-4) Menaquinone-4 menadione. as designated correctly and commonly used commercially but which is also somewhat unstable in mixed feeds. In the presence of excessof presence the In feeds. mixed in somewhatunstable also is which but commercially used (MSB) bisulfite 3.2),(Figure sodium menadione been product, addition has whichbisulfite sodium water-solublewater-soluble a Menadioneforms of this, used. because and are products, forms feed on the presence of lipids in the diet to promote absorption. There also are problems of its stability in Menadione itself possesses high biological activity in a deficient chick, but its effectiveness depends of Phylloquinoneforms menadionehave different expensive is too and used. been purpose, for this Chicks are very sensitive to vitamin K restriction, and diets. vitamin K swine extentin some is to and commonly poultry added in is to industry poultry diets. animal the in K vitamin of major use The 3.2.3.2 most active. the are series isoprenalogs menaquinone of the weight molecular high very [16],the protocol a as used is rats deficient to K vitamin of injection of assay may have been due to the relatively poor absorption of these compounds. When intracardial activity [15], maximum had groups lack the of and effectiveness type of isoprenalogs higher this in isoprenoidfive to three with isoprenalogs orally, administered When compound. reference the of that with compared active siteas the at compound effectiveness this ofand metabolism, transport, relative absorption, the of summation a course, were,systemsofassay whole-animal in K vitamin of analogs structural various of activity The chain. and polyisoprenoid side the ring, of the configuration to trans adjacent unit isoprenoid unsaturated an ring, the on group 2-Me a ring, quinone naphtho- following: a the included activity biological significant for essential be to found features various Structural forms. isolated in the of synthesized that with were compared was compounds activity biological their related and laboratories of number a K, vitamin of discovery the After 3.2.3.1 s 3.2.3 K vitamin called once was and chain side the in carbons 35 or units isoprenoid (2-methyl-3-farnesylgeranylgeranyl-1,4-naphthoquinone)3.1 7 Figure has in shown menaquinone [14]. bacteria offacultativeobligate anaerobic number by a and synthesized particular multiprenyl-menaquinonesare The that called chains side unsaturated with compounds K vitamin of series a F the vitamin K series, 2-methyl-1,4-naphthoquinone, was at one time called vitamin K vitamin 2-methyl-1,4-naphthoquinone,called series, K time of one at was compound vitamin the parent The series. this of members saturated partially several as well as identified, menaquinone-7 (MK-7). of Vitamins the menaquinone series with up to 13 prenyl groups have been Vitamin K Vitamin I GU RE

3.1 Analogs and and Analogs tructures Commercial Form of Vitamin K of Form Vitamin Commercial

Structures of some compounds with vitamin Kactivity. vitamin with of compounds some Structures Menaquinone-7 (MK-7)

Menadione of A O O O O T heir BiologicalActivity nalogs , C ommerc 6 i al F orms , 4 and O O O O Phylloquinone Menaquinone-4 (MK-4) 1 3 2 A ntagon i sts 2 3 3 but now is called called isnow but 3 but is more is but 91 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 92 a number of investigators but was finally isolated and characterized as 3 as and characterized isolated but was finally of investigators number a sweet in spoiled present clover compound by studied was had been that responsible fordisease this of consumption sweet cured improperly the clover to hay, and the in US was Canada traced described Midwest in the 1920s. cattle, The of disease hemorrhagic [19]. has A derivatives, Link by reviewed coumarin well the been K, vitamin of antagonists first the of discovery the of history The 3.2.3.3 (see countries Section 3.7.4). Asian for other Japan and osteoporosis in atreatment as utilized are MK-4,ofmenatetrenone, doses pharmacological WesternEurope, or States United the in used available shown been has and [18] orally. to effectivebe notAlthough whencurrently administered nowis MM, Konakion preparation, micelle” “mixed bilesalt and lecithin A notwell absorbed. are preparations these and promoted, been has K vitamin ofprophylaxis oral countries, some In born. new- injections ofprevent to the disease hemorrhagic intramuscular as used phylloquinone are and of preparations detergent-stabilized are preparations Mono-Kay. These and Mephyton, Konakion, as the desired form of the vitamin. Phylloquinone (USP phytonadione) is sold as AquaMEPHYTON, associated with menadione bilirubinemia usage (see Section 3.9) has led to the use of phylloquinone Synkayvite, was once used to prevent ofhemorrhagic disease the newborn, but the danger of hyper- water-solubleofform diphosphate,menadione, menadiol which sodium was sold or Kappadione as of MSB; to dimethylpyridinol bisulfite menadione pyridinol it[17]. is called widely used in industry.the poultry A water-solublethird compound is a salt formed by the addition is and it stability, complex increased (MSBC),bisulfite sodium has menadione complex,as known this bisulfite; sodium of mole additional an with complex a as crystallizes MSB bisulfite, sodium F Although warfarin is the most extensively used drug worldwide for oral anticoagulant therapy, 4 its as anticoagulant such derivatives oral coumarin for other worldwide drug used extensively most the is warfarin Although 3-( warfarin, been has factors rodenticide, clotting a as K–dependent subsequently vitamin and the of lowering long-term for clinically both these, of ful elsewhere.and in Link’s both most The were success- laboratory synthesized 4-hydroxycoumarins substituted numerous and studies, early some in therapy anticoagulant for used successfully was 3.3).Dicumarol (Figure dicumarol called was 1941 1933 and to from group Link’s by coumarin) used anticoagulant for 60 years, it does require routine coagulation monitoring and is, to some some to is, and monitoring coagulation routine require does it years, 60 for anticoagulant used reviewed by O’Reilly has the been K most as antagonist, widelya [20]. vitamin warfarin, Although havebeen interactions pharmacodynamic their of many and compounds these of use clinical The active site. the at antagonist K vitamin a as effectiveness their in presumably and half-life, plasma their in intestine, the from absorbed are they which to degree the in differ drugs These used. been I GU The clinical use of vitamin K is largely limited to various preparations of phylloquinone. A phylloquinone. of preparations various to limited largely is K vitamin of use clinical The RE

3.2 Antagonists of Vitamin Action of Vitamin Antagonists

Forms of vitamin K utilized in animal feeds. animal in Kutilized of vitamin Forms MSB O O 3H CH SO 2 3 – 3 O Na O O ′ -nitro analog, acenocoumarol, and phenprocoumon have phenprocoumon and acenocoumarol, analog, -nitro + CH SO MPB 3 3 –+ H H 3 C MSBC α O O -acetonylbenzyl)-4-hydroxycoumarin. -acetonylbenzyl)-4-hydroxycoumarin. OH NN SO NaHSO CH CH 3 – 3 Na 3 + 3 + ′ 3H ,3 ′ 2 Handbook of Vitamins Handbook -methylbis-(4-hydroxy- O Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 F anticoagulant- has coumarin 2,3,5,6-tetrachloro-4-pyridinol, compound, in unrelated anticoagulant effectivestructurally Another [28]. an rats is resistant it and site, active its at vitamin the of quinone resulted in a potent antagonist of K. Chloro-K vitamin acts like a competitivetrue inhibitor 2-chloro-3-phytyl-1,4-naphtho-form to atom chlorine a by phylloquinones of group 2-methyl the replacement of that [27] activity K demonstrated for vitamin requirements structural ofthe studies Early action. its antagonize to shown been have also vitamin the of analogs structural Some used. wereas and anticoagulants clinical rodenticides administered at one time, they are currently seldom they although and 4-hydroxycoumarins, the as mechanism same the by act to [26] appear pounds tion are the 2-substituted 1,3-indandiones such as 2-phenyl-1,3-indandione 3.4).(Figure These com- death. to lead can by or cats birds consumption of[25] as carcasses but care with should used be control rodent for used widelynow are brodifacoum and difenacoum as such Compounds strains. body much the from cleared more slowlyare rat effective are and rodenticides warfarin-resistant in 4-hydroxycoumarins of hydrophobicderivatives [24].More populations anticoagulant-resistant of [23]. consideration under for but does, excessivepotential the is still bleeding warfarin that extent monitoring of coagulation [21,22].the do not require anticoagulants havedrugs available as These become IIa, factor and Xa factor procoagulants, of the inhibitors direct are that recently,More by drugs diet. affected extent, F Vitamin K Vitamin I I GU GU Other compounds having anticoagulant activity that can be reversed by vitamin K administra- K vitamin by reversed be can that activity anticoagulant having compounds Other widelyhas been Warfarin as used a rodenticide, its use and has led continual to developmentthe RE RE 3.4 3.3

Other vitamin Kantagonists. vitamin Other Oral anticoagulants that antagonize vitamin Kaction. vitamin antagonize that anticoagulants Oral 2-Phenyl-1,3-indandione Phenprocoumon OH O Dicumarol HO OO O O OOO OH O O Chloro-K Cl 2,3,5,6-Tetrachloro-4-pyridinol Cl Cl HO HO Acenocoumarol Warfarin OH N 3 OO OO Cl Cl O O NO 2 93 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 phylloquinone the is the of those naphthoquinone largelyanalysisring. NMR of phylloquinone are has been used establish to that firmly natural that spectra absorption (NMR) resonance magnetic nuclear characteristic exhibitand also infrared compounds active K Vitamin peak. nm 270 the of disappearance and peak nm 245 the of enhancement an with hydroquinone, the to reduction upon drastically changes spectrum absorption The 19,000. approximately is menaquinones various the and phylloquinone value extinction molar The 320–330nm. around at absorption sharp less a and nm 280 of that is the nucleus,naphthoquinone characteristic trum with between and four240 peaks distinct spec- (UV) ultraviolet an exhibits vitamins K the of[31–33]. availableform readily oxidized The are menaquinones the and phylloquinone of characteristics physical other and special the on data the of much and quinoids of chemistry The quinones. all of expected properties chemical general the havetherefore, and, 1,4-naphthoquinones substituted are activity K vitamin with Compounds 3.2.4 Kantagonists. [30] effective also phenols polychlorinated other are vitamin that demonstrated have studies Subsequent vitamin. the of antagonist direct a as functioning is it that woulditappear rats, warfarin-resistant in action itsof basis [29], the activity on and anticoagulant 94 approximately 1 ng/ml ofapproximately 1 phylloquinoneng/ml [36], which is only 20%–30% of found that cow’s in contains milk. milk Human contributors. major [35],are oil rapeseed and oil soybean particularly oils, known for some time to be the major been source have ofK in vitamin vegetables the diet, it is leafy now apparent green that cooking Although a 9%–45%. and 7%–14% of of variation range of coefficient the between-sample in foods different for variation of coefficient within-sample a have wellas considerable as of data. unpublished amounts source, this from data contain reviewsalso may and texts older various in content K vitamin food Tables ofintake. calculate to used be not should and qualitative than more be to intended not was have apparently been in recalculated an unspecified wayfrom data obtained by a chick bioassay that publications valuesvarious previously ofin the 1990s.Many early quoted the available until made [34,35]. Kmetabolism tool investigate to vitamin analytical an as of use HPLC the to led ally eventu-tissues animal and serum in K vitamin of quantitation the in Interest decomposition. little with distilled vacuum be can and heat to and atmosphere oxidizing relativelyan to stableare they but sensitivealkali, to also are activity K vitamin with Compounds vitamin. the ofdecomposition separations All available. now are sources food involving most concentrated extracts of and K vitamin should outbe carried in serum, subdued light UV to minimize tissues, in present K vitamin of amounts small the for suitable methods Analytical techniques. (HPLC) chromatography liquid small the of they havedetermination by and high-performance sources, superseded been natural present in the ofamount vitamin in practical not therefore are methods simple These vitamin. the bebefore amount usedto can quantitate UV significant ofabsorption spectra is separation required a that such also is extracts crude in present substances interfering of number value.The analytical developed little [32,33], haveof been assaysthat are they colorimetric the of many with react also Chemical reactivity of K vitamin is a function of the naphthoquinone nucleus, and as other quinones 3.3 isoprenoid oflength the chain. from organic solvents be crystallized and have melting points from 35°C to on60°C, depending the easily can menaquinones various the temperature; room at oil Phylloquinone an sources. is natural from isolated series menaquinone the of vitamins of saturation of degree the and chain side the of length the determining in useful been has spectroscopy recently, mass More vitamin. the of tures Current methodology utilizes HPLC analysis of lipid extracts and has been reported [12] to to [12] reported been has and extracts lipid of analysis HPLC utilizes methodology Current not were foods consumed commonly various of content K vitamin the of tables Satisfactory

An P hys a lyti i cal ca

and isomer and can be used to establish the the establish to used be can isomer and trans l Pro C hem c i cal ed P u res ro p ert a nd Vit i es a min KContent o cis – ratio in synthetic mix- synthetic in ratio trans Handbook of Vitamins Handbook f Food for both both for ε Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 in Scotland, 72 and 64 64 and 72 Scotland, in 74 and 84 be to reported women havebeen and men adultfor Ireland in intakes none Vitamin K Vitamin mately 115 100 and [42], data III) wereadult USthe female approxi-and intakes male Survey (NHANES Examination Nutrition and Health National Third the on Based phylloquinone. of intakes daily average culate the aging. to action during [41]bacterial owing menaquinones long-chain of amounts appreciable have can cheeses some and found in meat poultry and egg yolk as rations poultry are commonly supplemented with menadione, are MK-4amounts of Significant UnitedStates. the in that than higher is substantially Netherlands the and China, Japan, in adults of intake phylloquinone the that indicate [40]that countries other of number a from published databases are there States, United the from data the with none.Along phylloqui- is reported, usually source the and foods, in K vitamin of source major The available. [12]are products food baby [39], and dishes [38],mixed foods fast of of databases content K foods, common vitamin the of reports the to addition In sources. major next the being oils cooking with vegetablesofvitamin, gov/fnic/foodcomp. the sources best leafy the and are green general, In http://www.nal.usda.at accessed be can foods of number large a of content K vitamin the taining diet study. total con- extensive Administration database An of Agriculture US updated Department Drug and US Food ofthe analyses from and fooditemsvalues for various HPLC-derived reported provided bythat milk. breast than intake higher much a providing K, vitamin with supplemented currently are formulas Infant Vitamin KContent of Vitamin Tab Parsley Kale Vegetables re nos27Safflower oil 207 Broccoli Green onions Endive Spinach Note: Cauliflower Carrots Tomatoes Cucumbers Peas 177 Cabbage Brussels sprouts Sweet corn Potatoes Beets Green beans Lettuce Mushrooms Onions Utilizing the available food composition data and food consumption data, it is possible to cal- to possible is it data, consumption food and data composition food available the Utilizing the of most considered that [37] literature of survey a from taken are 3.1 Table in data The

le 3.1 Values are taken fromaprovisional table[37]andaremedian values from acompilationofreportedassays. μ 4 Rapeseedoil 540 817 0 Sunflower oil 205 231 400 4 Drysoybeans 147 2 r inybas19 Drykidney beans 122 01Shredded wheat <0.1 9Raw peanuts Drynavy beans 19 36 7Sesameseeds 47 g/day. [43]. is previoussomewhat estimates than This higher phylloqui- Mean 5 5 6 . Dryspaghetti Wheatflour 0.5 0.8 3 2 μ O g/day [45]; in Britain, 70 and 61 and 70 [45];g/day Britain, in rdinary Foods rdinary μg Phylloquinone/100 gof Soybean oil Corn flakes White rice Walnut oil Olive oil Oatmeal Corn oil Bread N uts, Grains O ils, S eeds 193 141 <0.1 15 11 49 47 E 3 9 0.2 0.6 8 2 0.7 Cheddarcheese 1 3 3 . Mayonnaise 0.2 dible Portion μ g/day [46]; and in the Netherlands, 257 Netherlands, the in [46];g/day and Ground beef Cantaloupe 3.5% Milk Skim milk Egg white Egg yolk Avocado Bananas Oranges Chicken Apples Grapes Turkey Yogurt Butter Tuna Pork M eats and Fruits D airy μ g/day [44];g/day <0.1 <0.1 <0.1 <0.1 <0.1 40 81 0.1 3 1 0.5 0.1 0.1 7 2 0.3 3 0.5 0.3 95 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 form of the vitamin has some biological activity, the degree of this response has not been well been not has response this animals. subjects or experimental either human in ofestablished degree the activity, biological some has vitamin the of form [52]. diets this Although American in K vitamin total the of 20% around represents form genated of contribution of[50,51].the large high-phylloquinone phylloquinone vegetable Because of hydro- amount the oils the to diets, many unmodified of amount the exceed can margarines, harder the omto o sbtnil mut o 2 of amounts substantial of formation only 10 contain μ that diets adequate nutritionally formulate long-chain menaquinones to anticoagulated human subjects human [65] long-chain to menaquinones anticoagulated effectively extentthe of decreased mixed mg 1 of administration oral lowerbowel.The the from absorbed are of membranes constituents bacterial as present are that compounds lipophilic very these how is remains that question major a but observed, concentration increased the for account wouldphylloquinone,which of that slowerthan is menaquinones long-chain of turnover hepatic the [64]that evidence some is There [63].K livervitamin total 10% approximately the onlyof represents which concentration, quinone phyllo- menaquinones, the exceedsMK-7, long-chainMK-6, greatly mainly also MK-10,ofliver MK-11, human and amount in present total The contributors. major the MK-10 being and MK-9 with 5.1 mg to 0.3 from range [62]to reported been have colonoscopy patients five from tract contents intestinal total in found amounts the and large, quite be can gut the in K vitamin of amount 160 to 84 100 approximately contain can result in large differences. In a study where four metabolic ward diets to wereanalyzed directly diet the to vitamins most the contribute that fewfoods those of content K vitamin assumed the in 20 approximately and and and 244 244 and 96 menaquinones, menaquinones, but obligate anaerobes of the nones. Relatively few of the bacteria that comprise the floraintestinal normal are major producers of [61]. studied individuals the 5% between difference alarge with approximately was absorbed vitamin of amount the kale, from K vitamin of absorption the assess to used was methodology this when that [60] and bioavailability on impact substantial a has meal of type the that found been [57–59].has methodology,itfoods this from Using K vitamin of tion More recently, stable isotope-labeled phylloquinone has been used to sources. assess vegetable the bioavailable from phylloquinone absorp- than bioavailable more be may forms [41] these tions that Japanese market, do amounts substantial ofcontain long-chain menaquinones, and there are indica- the in mainly consumed natto, product, soybean fermented [54–56].a diets and Somecheeses free fat- in less much and fat substantial contained diets the when 10%–20% by absorbed be to found somewhat variable. Human subject studies of phylloquinone absorption from vegetablesgreen were insufficiency, by caused obstructive jaundice,absorption pancreatic disease. adult celiac or 80% of the ingested phylloquinone was excretedin the feces unaltered offat patients with impaired of 20% excrete (1to large a less than mg) dose of feces, but much phylloquinone 70%– as the as in weresubjectsfound [53] human Normal saturable. and dependent phylloquinone beledenergy was the presence of required bileboth juice and pancreatic and that the absorption ofstructures radiola- micellar phylloquinone-containing these that demonstrated studies Early micelles. mixed into tion The absorption of nonpolar lipids, such K, into as the lymphaticvitamin system incorpora- requires a 3.4.1 3.4 The conversion of liquid oils to solid margarines by commercial hydrogenation results in the the in results hydrogenation commercial by margarines solid to oils liquid of conversion The Substantial Substantial amounts of vitamin K are present in the human gut in the form of long-chain menaqui- been have sources food different from phylloquinone of bioavailability the of studies Early m groups are, as are facultatively anaerobic organisms such as as such organisms anaerobic facultatively are as are, groups Arachnia μ et g/day [47]. consumption of high ofprovides The also Netherlands the intake cheese in an bsor μ ab g/day [48]. Use of the current database information has, however, made it possible to to possible it however, made has, information database current the of [48].Use g/day olism p t i on μ g/day of long-chain menaquinones. As different databases are used, variations variations used, are databases different As menaquinones. long-chain of g/day

and T μ rans g/day, the amount calculated by two different databases ranged from from ranged databases different two by calculated amount g/day, the p ort

of ′ ,3 V ′ dhdohlounn, hc, n h cs o sm of some of case the in which, -dihydrophylloquinone, i Bacteroides Bacteroides fragilis tam i n K g/day of phylloquinone [49]. , Eubacterium Handbook of Vitamins Handbook Escherichia coli Escherichia , Propionibacterium . The The . , Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 Vitamin K Vitamin very rapidly.very also consistent are3 in days.pool with afindings size ofoversmall These phylloquinoneturns that lostwas phylloquinone hepatic of two-thirds approximately that [72], indicated surgery to prior K of approximately 100 size pool body 1.5ofapproximatelya [71] turnover days and pool these body a consistent with are the disappearance of (<1amounts small the disappearance assessing data available limited only are There rapid. is turnover the that indicated phylloquinone radioactive of doses [53]pharmacological pool studies using early body and human small, very istotal phylloquinone of The available. not are organs between vitamin the of movement the and with apoE2 having slowest the of ofrate of secretion removal. phylloquinonethe liver from Details circulation the from chylomicronremnants of clearance hepatic the to correlated is response This concentrationshave genotype:shownapoEaccordingapoE4. decrease beentoapoE3to > apoE2 > quinone concentrations in patients undergoing hemodialysis therapy [70], and plasma phylloquinone (apoE) receptors. The polymorphism of apoE has been found to influencethe fasting plasma phyllo- of entry phylloquinoneof into tissues to route appears be via majorclearance of chylomicron The byremnants [70]. levelsapolipoprotein E lipid plasma with correlated strongly are concentrations phylloquinone plasma transport, lipoprotein from expected As MK-4. or phylloquinone either of high- the in found density were MK-4 lipoprotein fraction, and the of half-life of amounts MK-9 significant was found K, to be substantially greater than that vitamin of forms different of transport the [66]comparing study [68,69].a fraction In low-density lipoprotein the in located are amounts lipoprotein fraction very containing low density lipoproteins and chylomicrons, although significant triglyceride-rich the by carried predominantly is [59].plasma in Phylloquinonedetail reviewedin MK-4, to abiologically alkylated be it active can absorption, vitamin. formof the colonthe and by a passive [67].process Menadione itself does not have biological activity,intestine small but after the both from absorbed be can It K. vitamin of source a as diets animal laboratory but it is likely to be less that than of phylloquinone. Menadione is widely used in poultry, swine, and data, these from determined be cannot menaquinones overallbioavailabilityofthe phyl-The loquinone. of 20% than less was menaquinones serum the of concentration peak the males, healthy to has been shown [66] that when equivalent oral doses of phylloquinone, MK-4, and MK-9 were given [62]. It studied. carefully bioavailability not has been food The ofpresent in sources menaquinones occur could absorption acid–mediated bile where region a in bowelbut large the in not located is bowel. However, content but a intestinal the portion theofsmall vitamin of significant nutritionally large the from absorption their address not does but intestine small the from vitamin the of forms these absorb digestive can human tract the that demonstrating hypoprothrombinemia, acquired the concentrations concentrations do respond to daily changes in and intake fall rather rapidly when is intake restricted day’ssingle a phylloquinone from Circulating plasma.individual of sample an of status K vitamin the determine to attempts in used other be shouldcaution extreme the this, of forBecause fat-soluble vitamins. that than higher much is subject same the from days different at measured samples positive strong a correlation between plasma triglycerides plasmaand is phylloquinone [78], There (1.1 between variation the and nmol/L). ng/ml 0.5 around are values fasting normal that appears [58,76,77]. spectrometry at lower use of the HPLC/mass measured been through has loquinone concentrations phyl-deuterium-labeled and reduction, postcolumn zinc after involves detection time fluorescence present the at methodology [73–75]. methodologyused commonly mostthis replaced The has tion chemical detection or fluorescencedetection ofthe after vitamin chemical or reduc- electrochemical sensitivity;electro- lacked that detectors UV utilized HPLC by K vitamin of measurements Early 3.4.2 Absorption Absorption of phylloquinone from the intestine is via the lymphatic system and has been recently Although earlier reports of plasma phylloquinone concentrations were somewhatwerenowithigher, phylloquinoneconcentrations plasmaof reports earlier Although P lasma C oncentrat μ g. Other data, based on liver biopsies of patients fed diets very low in vitamin i ons

of V μ i g) of infused tam i n K 3 H-phylloquinone subjects,from human and 97 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 t 3.4.3 Kis, however, of vitamin source human nant vegetables phylloquinone green [11]. from oils and predomi- The cheeses. hard and soft both in found are menaquinones longer-chainof range a and meat, chicken and yolks egg in found are MK-4 of amounts significant rations, poultry in used is eaten only in that region where it can provide more K vitamin than phylloquinone. When menadione growing by produced is It Japan. eastern in levels [82,83]. One menaquinone, MK-7, is present in high concentrations in natto, a foodtraditional nones, they detectable are in plasma menaqui- and, in some cases, havelong-chain to been present reported of at substantial amounts appreciable containing foods few very are there [81]. Although ethnicity and race to according differ does status K vitamin the States, United [79,80]. the Within 98 be MK-7, be MK-8, MK-10, MK-11. and sources potential are long-chainmenaquinones the Although (Table a that broad mixture 3.2) of is menaquinones present [72]. to forms appear predominant The and pool K vitamin total the 10%of approximately only represents phylloquinone that shown has liverspecimens human of found number recently,Morelimited liverspecies. are a mostofof analysis the in chain alkyl the in units prenyl 6–13 containing menaquinones this, to addition in that, and material plant ingesting species those ofliver the in found is phylloquinone that indicate data available,these and are data limited Only species. different from tissue in present are vitamers the fraction. subcellular amicrosomal than rather mitochondrial a in [88] available, preferentiallyMK-9 localized be are to reported and ofmenaquinones been has distribution the on data limited Only fractions. membrane microsomal smooth and Golgi the in be tions.study A [87]more detailed found activity highest specific the ofradioactive phylloquinoneto frac- debris cellular and mitochondria the in found amounts substantial with fraction, microsomal the recoveredin was liver radioactivity the of50% than more phylloquinone [85,86]that indicated radioactive utilizing Studies lost. rapidly is[84], it10–15 h of range the in be to appears liver the half-life in the but as points, time early at vitamin of majority the the liver wasThe found retain to phylloquinone. of physiologicalamounts more excessive and both utilizing vitamin, the of forms radioactive with studied first was rat the of organs body various in K vitamin of distribution The Because Because of the small amounts oftissues, K itin vitamin animal is difficultwhichto determine of i ssue D i Vitamin KContent of Human Vitamin a Phylloquinone Vitamer Tab MK-7 MK-6 MK-5 MK-8 MK-9 MK-10 MK-11 MK-12 MK-13 str

recalculated from data presentedasng/gliver. NR,notreported. been have B and A studies Values[72]. from C study and [236], B study [235], study A study: each in subjects 7 or 6 for SEM Values± means are i but le 3.2 i on

of V i tam 95 ±157 S i 57 ±59 12 ±13 12 ±18 67 ±71 90 ±15 15 ±13 n 22 ±5 tudy A 2 ±4 5 ±6 K pmol/g on cooked soybeans and is essentially essentially is and soybeans cooked on natto Bacillus L L iver iver a 2 134±12 122 ±61 S 6±1 75±10 96 ±16 4±3 99±15 94 ±36 8±428±4 18 ±4 1±29±2 11 ±2 1±614±2 21 ±6 tudy B 4 ±2 8 ±3 NR NR S tudy C 2 ±1 5 ±1 NR NR Handbook of Vitamins Handbook Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 ramn wt cuai atcauat. h dsrbto o te aiu uiay eaoie of metabolites urinary various the of distribution after The vitamin anticoagulants. the of form coumarin with predominant the treatment become can amount this that and epoxide the as ent pres- is rat normal a of liver the in K vitamin the of10% approximately that this revealed of compound studies Further liver. the in K vitamin radioactive of buildup that a [85] caused treatment observation warfarin an investigating was who [100] Matschiner by discovered was metabolite s 3.4.4 phylloquinone.than MK-4 more much contain [89]shown to been also have gland, salivary and pancreas particularly rat, the tissues MK-4,of of amounts but some nonhepatic significant have species ous detected not vari- from liver of analyses Most tissues. some of requirements K not-yet-defined unique, vitamin the satisfying in role in a playmay MK-4 present that havesuggested data Recent are concentrations. equal compounds in liver two the when phylloquinone as extensive as 20% approximately only be [88] to shown been has carboxylase K–dependent vitamin the utilization for substrate The a known. as MK-9not of is utilized are they which to extent the liver, in activity K vitamin of uct of the action of the vitamin K–dependent vitamin the of action the of uct [99]. of excretion amount phylloquinone The changes to related in was intake. also it was found approximately excretionthat 75% was form the ofin 5-C-aglyconethe urinary of total youngutilizing adults consuming a control diet, a phylloquinone-restricted diet, and a repletion diet, [59]. degradation tocopherol study in controlled a seen as In manner same P450 the cytochrome in is likely that the initial aglycone has a 7-C side with a chain 1 3.5). One aglyconesconjugatescarboxylictwo (Figure of glucuronide the phylloquinonecomprise of metabolites the studies, human and rat both bile.In the via feces the in excretedwas 40%–50% that and days 3 in urine the in excreted was K vitamin of mg 45 or 1 either of dose injected an of 20% approximately that indicated humans in phylloquinoneradioactive of metabolism [53] the of excretion Subsequentstudies present. phylloquinonewas of unmetabolized little route very that and majorfeces the in was the that demonstrated [97] metabolism phylloquinone of studies Early m 3.4.5 of MK-4 aspect synthesis. this clarify to needed be will studies additional prenylation step maya and second enzyme be involved sideremovingin However, initial chain. the a also of function Some enzyme. same [96] the recent data suggest UBIAD1that only catalyzes the itand cleavage side-chain suggestedhas been initial the of phylloquinone or is menaquinones other [95],MK-4prenylation to menadione ofthe catalyzes that nyltransferase(UBIAD1)enzyme the is pre- human a that demonstrated has study [94].recent MK-4 more A administering by than tation by rats phylloquinone in supplemen- obtained of moretissue readily concentrations high MK-4 are that established been has it [93], and tissues human in observed been haveMK-4 of distributions of tissues exceed those phylloquinone. that MK-4 in concentrations the and Similar gland, salivary [91,92]. used phylloquinone-to-MK-4pathwayThe conversion is the very extensive and rat tissues pancreas, in suchbe brain, as to not found been has This menadione. resulting the of prenylation actionone bacterial might time that to intestinal be removerequired the side chain that would allow phylloquinone and other long-chain removalmenaquinones after of the side chain. It was thought at be synthesized by prenylationdirect of menadione, the majority of this menaquinone is formed from vitro incubation of liver homogenates with in geranylgeranylby pyrophosphateor [90]. Although MK-4 can administration oral after MK-4 to converted be pathway.can Menadione alternate an by [14]. However, MK-4 is not a major product ofmenaquinone biosynthesis, bacterial and it is formed byLong-chain menaquinones synthesized are via bacteria pathways that have been well established Vitamin K Vitamin The The most abundant metabolite of phylloquinone is its 3.5)(Figure 2,3-epoxide formed as a prod- ynthes etabol i s i

c of D M ω egradat -oxidation step to the initiate degradation of the side out chain is bycarried K-4 i on

of ′ ,2 V ′ double side has a other [59,98].bond, the 5-C and chain It i tam i n K γ -glutamyl carboxylation (see Section 3.6.3). This 3.6.3).This Section (see carboxylation -glutamyl 99 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 dent and, therefore, plays an anticoagulant rather than a procoagulant role in normal hemostasis normal in role procoagulant a than rather anticoagulant an plays therefore, and, dent 100 protein demonstrated to contain to protein demonstrated contain itfirst the was also future, the in and discovered. proteins, oftor to be Itmost these is abundant the protein (also of This prothrombin. clotting called factor was II) the first plasmaprotein clotting fac- concentration decreased a contained chicks these of plasma the that demonstrated was it extracts, Soon Dam’safter discovery of a hemorrhagic condition in chicks that could be bycured plant green 3.5.1 3.5 Kstatus. noninvasive auseful be might of metabolites of vitamin marker these quantitation that suggested been has it [102],developed and been has K vitamin of aglycones urinary majortwo the of analysis routine forthe useful is that Methodology yetcharacterized. not products biliary and urinary of number a be may there but menaquinones, from or phylloquinone K to ofmetabolism haveappear vitamin been identifiedandarethen apparently eitherfrom formed products degradation major The increased. are epoxide, the from arising presumably metabolites, [101], decreased uncharacterized are other 3.5) and (Figure glucuronides urinary major chain side 5-carbon and 7-carbon The administration. bywarfarin altered substantially also phylloquinoneis F involved in a [105] are thrombin-initiated S inactivation protein of [104] and factor C V Protein discovered. were homology similar with proteins plasma position prothrombin. in as same the essentially in are each in 10–13residuesGla the homologous, and very is procoagulants to converted γ posttranslationally been have that residues acid glutamic of number a contains that each domain with amino-terminal byan complexescharacterized are proteins These proteins. membrane-associated accessory with and other through events propagation and activation these in involved are factors clotting K–dependent vitamin The zymogens.pro- by protease of thrombin activation of teolytic generation the to lead that 3.6) (Figure events of series complex a involves synthesis. for their vitamin this require to known only proteins the were factors” clotting K–dependent “vitamin four mid-1970s,these the Until synthesis. their [103]disorder bleeding with a hereditary were and subsequently K forshown to depend on vitamin and IX, X were identifiedinitially theirbecauseall activity in the was decreased plasma of a patient 1,4-naphthoquinone and the 5C-aglycone 2-methyl-3-(3 the is and 1,4-naphthoquinone I -carboxyglutamyl residues (see Section 3.6). The “Gla domain” of the four vitamin K–dependent vitamin four the of domain” “Gla 3.6). (see-carboxyglutamylresiduesThe Section GU After the discovery After of Gla residuesmore K–dependent Gla-containing proteins, in three vitamin plateletactivation, with along and, forhemostasis essential is coagulation bloodof process The

RE Vit 3.5 P lasma a

min K– Phylloquinone metabolites. Phylloquinone The metabolites. 7C-aglycone is 2-methyl-3-(5 C lott D i e ng O O p 7C-aglycone endent Proteins F actors γ -carboxyglutamic -carboxyglutamic acid (Gla) residues. Plasma clotting factors VII, Phylloquinone-2,3-epoxide O O COOH O ′ -carboxy-3 a , a clotting factor that is not vitamin K depen- O O ′ -methylpropyl)-1,4-naphthoquinone. 5C-aglycone 3 ′ -carboxy-3 Handbook of Vitamins Handbook COOH ′ -methyl-2 ′ -pentenyl)- Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 Vitamin K Vitamin to limit clot formation. limit to contains four epidermal growth factor domains but is not a serine protease. The function of function protein but The factorprotease. is notdomains growth a fourserine epidermal contains S protein while domain, protease serine a and domains factor” growth “epidermal two contain C that are also found in plasminogen and a protease serine domain. Factors IX, VII, and X and protein have other common features. The Gla domain of is prothrombin followed by two domains “kringle” proteins K–dependent vitamin the domain, Gla 40-residue approximately the to [106].addition In cofactor (circles) to form a Ca activations of series protein plasma additional an this and substrate, protein K–dependent in involve vitamin a second active an protease, steps of number A clot. fibrin insoluble the to fibrinogen soluble of conversion zymogen, and effect cascade this results in the rapid activation ofto and the subsequent thrombin prothrombin exposes injury tissue factor vascular to blood. The product of the activation of one factor can activate a second by pathway “extrinsic” an activewhen be initiated to (subscript their can converted a)process are This forms. they when initiated is F-X. and Coagulation F-VII, F-IX, prothrombin, proteases; serine ofthe zymogens are F agulants. Protein C is activated by thrombin (II thrombin by activated is C Protein agulants. not proco- control in as hemostatic anticoagulants, Two F-IX. participate subsequently proteins K–dependent vitamin other and F-XI of activation thrombin involving pathway “intrinsic” an through occur also can F-X bomodulin (TM). Protein C is then able to function in a C in able complexV is S then to to inactivate function protein with Protein (TM). bomodulin I GU RE 3.6

Vitamin K–dependent clotting factors. The vitamin K–dependent procoagulants (gray ovals) (gray procoagulants K–dependent vitamin The factors. clotting K–dependent Vitamin Factor X Fibrinogen 2+ -mediated association with a phospholipid surface. The formation of formation activated The a with phospholipid association surface. -mediated PL Ca Prothrombin 2+ Tissue factor Ca rombin Factor VII PL 2+ VII X a XII X II a a a a Ca a ) in the presence of an endothelial cell protein called throm- called protein cell endothelial an of presence the in ) PL Fibrin 2+ V a Ca 2+ Factor X Factor IX (Inactive) II a IX V V a Ca Ca VIII 2+ 2+ a XI a (Inactive) Protein C II Protein S Protein C a VIII VIII TM II Ca a 2+ a XI a and VIII and a and and 101 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 maturation of human bone mineral [114]. In most species, circulating osteocalcin is fully carboxy [114].fully is mineral osteocalcin bone circulating human of species, most In maturation at puberty. levelsadult approach and children young in high are that concentrations at plasma in appear does bone in produced formation.Someosteocalcin defect bone a of the in than rather bone dense more [113]shown produce to been have mice “knockout” gene However, turnover. osteocalcin skeletal or is involved control of the tissue mineralization osteocalcin in that tions someindicate manner in and fusion months, of 2 the tibiaproximal growth plate was after observed 8 after months [111,112].normal of 2% approximately to decreased These observa- was osteocalcin bone when bone seen in were defects no protocol, this Utilizing production. protein K–dependent vitamin plasma tain fed and a also given diet the warfarin anticoagulant containing large amounts of K vitamin to main- to difficult very been has are function rats be blocked when can biologicallythe active its define. of “Gla Synthesis osteocalcin of form” bone, in protein abundant most second the is it Although proteins. plasma K–dependent vitamin the homology to or structural little had osteocalcin and protein, Gla bone called was residues, Gla three contained protein [109,110]. 49-residue bone This discovered protein that K–dependent inwas vitamin not first plasma located The from was isolated c 3.5.2 disorders coagulation riskin have [108].factors as proteins of identified these been variants cDNA and genomic organization of each of the them is extensivelywell studied, documented, and been a have large number they of hemostasis, genetic in role critical a play proteins these As tions. shownnowsome condi- but [107]has for under been sometime, function have to anticoagulant an Z, the seventh plasma Gla-containing protein, which is also not a protease zymogen, was not known 102 this problem. this to directed is MGP with of role the individuals define of to effort current the status K low,of muchis disease kidney chronic vitamin the [132,133]. As calcification vascular of decrease the in responses supplementationhavephylloquinoneminor shown utilized that studies intervention and sue calcificationandthe prevention calcification ofarterial [130,131]. MGP is notfullycarboxylated majorthesuggest findings that recent roles involvement are of its MGP regulation the tis- ofin soft model rat [129]. More warfarin-treated a in demonstrated been has calcification [128],arterial and cartilage and arteries of calcification spontaneous from die mice knockout MGP that shown been physiological unclear, ofthis butit has roleare details insolubility,The aggregate. to tendency and tobecause soft oftissues. study other difficult many MGP its been has hydrophobicrelative nature, butosteocalcin is also present in other tissues and has been shown to be synthesized and in cartilage to related structurally is protein (MGP). This protein Gla matrix the [127]called bone is from and is not yetprotein available. K–dependent vitamin this of impact hormonal the of understanding an and responses, [125,126]resulted variable have in homeostasis glucose and resistance insulin on osteocalcin of impact the of studies [124]. form Human uncarboxylated the was osteocalcin of form hormonal the that was levels [123].glucose tolerance insulin and reduced finding and unexpected lipidconcentrations An and glucose elevatedfound mice knockout osteocalcin the of studies Initial function. hormonal a have may osteocalcin that indications some also are elderly. There the in loss bone the ofprevention for K vitamin supplemental promote to sufficient be to seem not do they results, various had and adults older [121,122]. studies in similar and have loss these efforts on these based Although meta-analyses somebone also of progression the slow will K vitamin with supplementation that hypothesis the [117–120] tested studies have that clinical controlled randomized of number large [115,116].supplementation a and repletion, been depletion,have K There vitamin to respond that lated, but in healthy humans, there are substantial amounts of undercarboxylated osteocalcin (ucOC) The three Gla residues in the osteocalcin structure are critical for the role of this protein in the the in protein this ofrole the for critical are structure osteocalcin the in residuesGla three The A second low-molecular-weight (79-residue) with protein five Glaresidues alsofirstwas isolated alc i f i ed T i ssue P rote i ns Handbook of Vitamins Handbook ­ Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 Vitamin K Vitamin amino acid. amino modified this synthesizing ofcapable organisms of range wide the within discovered be yetto are proteins K–dependent vitamin numerous that and origin evolutionary ancient of is of acid modification glutamic posttranslational this that suggests systems phylogenetic of homology these sequence from strong enzyme The [149]. the archaea and bacteria of genome the in identified been a number of vertebrates, the the vertebrates, of number a from cloned been [144,145].venoms has snake carboxylase in The found been also have proteins marine by secreted peptides Gla residues. shown be contain to will proteins other time, in that, role is not known. The K–dependent vitamin carboxylase is metabolic a major substrate Its for associated. itself [142], matrix extracellular and be it to is [141], likely appears protein it and containing Gla- a be to found was it before protein known previously a been had periostin, protein, Another known. not yet are receptors cell-surface these cloned[140]. role have of the been of specifics The TMG-4) (TMG-3and family Glaprotein Subsequently,transmembrane ofthis members twoother residues. Gla in rich is that domain amino-terminal extracellular an with proteins membrane gral PRGP-2)[139]inte- (PRGP-1discovered and as were[138].proteins Gla cancer Two proline-rich and vasculativeintegrity,thrombosis, atherosclerosis,immunity, in roleits of indications are there but fordefined, clearly not factoris protein growth the physiologicalof function The a cells. epithelial be and to mesangial appears [137],which Axl kinase tyrosine the for ligand a 6, Gas is ied extensivelymost The stud- synthesis. their for K vitamin [11]dueson dependent therefore are and resi-Gla have contain shown to nowproteins been mammalian relativelyofother A number small o 3.5.3 with 15–16 protein small Gla itresidues most makes the densely that protein synthesis. protein notrequire did that step a in prothrombin to converted be could that and synthesized rapidly being was that rat hypoprothrombinemic the in pool protein ofprecursor hepatic a presence the with tent inbovine was demonstrated plasmafirst by Stenflo [152], other and observationsprothrombin [153]of form were consis- inactive circulating A activity.biological lacked but prothrombin to similar wasantigenically that protein a contained anticoagulants coumarin with treated plasmaofpatients [151] the demonstrated subsequentlythat was It prothrombin. plasma of form inactive circulating a to due was patients anticoagulant-treated in time clotting abnormal an [150]that postulated who al. et Hemker by stated clearly first was prothrombin ofbiosynthesis the in precursor intracellular tran- a wereInvolvementconsidered. hypotheses level at proven, alternate scriptional ofbe an not could and proteins specific of production the controlled K vitamin that theories Early K. of role vitamin metabolic the of understanding an to led eventually animals production experimental and prothrombin humans of in studies 1960s, early the in deter- Beginning the role. and metabolic K its of vitamin mination of discovery the between elapsed years 40 approximately of period A d 3.6.1 3.6 or skeletal development stabilization, tilage but definitivehave functions not been identified. yet availability,car- calcium of modulator a as [136]. function mice may Itnull in reported havebeen alterations obvious no phenotype and clearlydefined, yet notbeen [135]. has GRP of function The humans and mice in been found also has but sturgeons in found first was protein The date. to fied Vitamin Vitamin K–dependent proteins are not confinedto vertebrates. A large number ofthe toxic venom (GRP) a Gla-richprotein is the discovered[134] recently more protein, A K–dependent vitamin

Bio i ther ch sco v emi V ery i tam

ca of i

n l γ K– - R C ole o arboxyglutam D snail, a tunicate, zebrafish, and zebrafish, tunicate, a snail, Conus snails are rich in Gla residues[143],Gla in K–dependent rich are vitamin snails and Conus ep endent f Vit P a rote i min K c A i c ns i d [146–148], Drosophila has and γ -carboxylated protein identi- protein -carboxylated 103 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 K-2,3-epoxide. CO Glu residues in the first 33 residues of prothrombin are modified in thisfashion. in Glu are modified first residuesresidues 33 the in prothrombin of the 10 all that al. [157],demonstrated who et Magnusson by confirmed were prothrombin in dues (residues 33 and 34 ofacid of glutamic prothrombin), resi- modified the characterizations and these as present were they that so modified were peptide this of residues acid glutamic the that demonstrated and prothrombin) of 6–9 (residuestetrapeptide acidic an al. isolating in et [155]Stenflo bin. succeeded not prothrom- were ofisolation applied abnormal to preparations procedures whencould similar obtained be but prothrombin bovine normal of domain amino-terminal the of digest tryptic a from Nelsestuen et al. [156] independently characterized [156] al. characterized et Nelsestuenindependently carbon carbon dioxide rather than terms of enzyme–substrate recognition. a of terms enzyme microsomal recognizes This small fraction enzyme–substrate of the effective MK-6 MK-8, all and substrates. are vitamin, of forms the intestinal predominant the and MK-4, phylloquinone, measured, be can activity carboxylase in differences 104 ht rmtd vtmn –eedn icroain of incorporation K–dependent vitamin a promoted that carboxylase)K–dependent vitamin (the activity enzymatic an contained liver preparations rat microsomal crude [158] that demonstration the to led prothrombin in residues Gla of discovery The t 3.6.2 Ca Acidic, X. factor by prothrombin of activation stimulated phospholipid- the for needed are which ions, calcium to bind to protein abnormal the of inability the was proteins two these in difference critical The prothrombin. normal did as salts ublebarium acidcomposition, insol- to butweight not adsorb did molecular amino same and the had thrombin, F and the energy to drive this carboxylation reaction is derived from the oxidation of the reduced reduced the of KH oxidation (vitamin K of vitamin hydronaphthoquinoneform the from derived is reaction carboxylation this drive to energy the and ATP, require not does reaction carboxylation K–dependent vitamin The carboxylase. unique this Val [160], were for found enzyme substrates be to the of properties were they study to the and used Phe–Leu–Glu–Glu– as such sequences Glu–Glu adjacent containing peptides 3.8). Small (Figure vitamin K–dependent proteins present in these preparations. The same microsomal preparations preparations incubation CO fixed conditionsand that microsomal same The preparations. these in present proteins K–dependent vitamin I GU Normal functioning of the vitamin K–dependent carboxylase poses an interesting question in in question interesting an poses carboxylase K–dependent vitamin the of functioning Normal Studies of the inactive “abnormal” prothrombin [154] demonstrated that it contained normal normal contained it that demonstrated [154] prothrombin “abnormal” inactive the of Studies 2 , the enzyme converts a protein-bound Glu a residue to protein-bound a converts enzyme the , RE 3.7 − O H 2 he γ C R

-carboxyglutamic acid (3-amino-1,1,3-propanetricarboxylic3.7).acid -carboxyglutamic residuesacid)(Figure V O The vitamin K–dependent carboxylase reaction. In the presence of reduced vitamin K, O ofIn the carboxylase reaction. presence K–dependent vitamin reduced vitamin The i tam C H CH NH 2 i n H K– S D HCO ep endent 3 − OH OH O is the active species in the carboxylation reaction. Although some CO 2 C 2 CH R arboxylase 2 3 into Gla would convert vitamin K to its 2,3-epoxide [159] its Kto Gla 2,3-epoxide into would convert vitamin γ -carboxyglutamic acid (Gla) from a dipeptide (Gla)dipeptide acid a -carboxyglutamic from H γ 2 -carboxyglutamyl residue and generates vitamin vitamin generates residue and -carboxyglutamyl ) byO ) S + CO H 14 2+ 2 to form vitamin K-2,3-epoxide, and vitamin form to -binding peptides could be isolated be could peptides -binding 3 − no noeos rcros of precursors endogenous into O O Handbook of Vitamins Handbook − R CH O O − O 2 C 3 2 C O H C CH NH 2 H 2 , and Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 unity at high CO athigh unity approach to and concentrations substrate Glu of independent be to shown been cleaved has bonds enzyme by decreasing the apparent apparent the decreasing by enzyme the of activity [162,163] shownthe been modulate [161] to also has enzyme “recogni- and the or for site”“docking” tion a be to appears region This peptide. signal the and protein mature the of products of a these all proteins contain very homologous “propeptide” between the amino-terminus gene primary the revealedthat has proteins K–dependent vitamin ofthe Cloning proteins. these in protein total secretory pool of the appropriate tissue and then carboxylates all the available Glu sites of a formation F have not been identified in the enzyme-catalyzed reaction but are postulated on the basis of model organic organic model presence. of their with consistent basis are available data the The reactions. on postulated are but reaction enzyme-catalyzed the in identified been not have this reaction are vitamin K-2,3-epoxide and a vitamin ofare reaction Attack this glutamyl CO carbanion. the abstract to basic sufficiently is that metabolite ated oxygen- to an leading eventually intermediates generates K, of form vitamin (hydronaphthoquinone) reduced on the are sites Glu result event ofall the onecarboxylated binding as [164,165].which in mechanism processive a through occur to known is carboxylation full residues.Gla However, to converted Glusitesare all until mechanism distributive a in times many carboxylase the from dissociate and bind could they substrates, protein K–dependent vitamin the Vitamin K Vitamin the role of vitamin K. The reaction efficiency defined as the ratio of Gla residues ratioto of Gla the as formed efficiency reaction defined The K. role ofvitamin the which epoxide formation is coupled to lent stoichiometry between K-2,3-epoxidevitamin formation and Gla formation. The mechanism by of tritium from the substrate, and at saturating concentrations of CO of concentrations saturating at and substrate, the from tritium of [166,167].KH involved vitamin a stoichiometry catalyzes enzyme the The and action the of information initial the provided residue Glu each of of the to vitamin its 2,3-epoxide. A number of studies that substrates utilized tritiated at the I GU The roleThe K ofin the overall vitamin reaction by catalyzed is the enzyme to abstract the hydrogen RE γ O OH 3.8 -carbon of -carbon the glutamyl residue to allow ofattack CO − HO R CH

O O 2 3 γ The vitamin K–dependent K–dependent vitamin The -carboxyglutamyl residue (Gla). The bracketed peroxy, dioxetane, and alkoxide intermediates residue (Gla).-carboxyglutamyl peroxy, intermediates alkoxide bracketed and The dioxetane, O Vitamin KH 2 R CH concentrations. O OH 3 OH − R CH 2 3 HO K − m γ O γ O -glutamyl carboxylase. An interaction -glutamyl of carboxylase. An interaction O of the Glu site substrate. As there are multipleonGlu sites are there As substrate.Glusite the of H -hydrogen abstraction is key to a completeof understanding O 2 R − C O O CH R Glu CH C H 3 HO NH 2 2 – and O and – H O 3 O γ − -hydrogen of the glutamyl residue. The products of products The residue. glutamyl the of -hydrogen O R CH 3 2 -dependent (but CO (but -dependent 2 at positionthis coupled to conversion Vitamin Kepoxide 2 , there is an apparent equiva- apparent an is there , 2 on the carbanion leads on to the the carbanion O O H OH 2 O CH R + S 2 -independent)release with vitamin KH with vitamin − 3 − − − O O O 2 2 C H 2 C C γ CO O O -carbon -carbon Gla γ 2 H H CH C CH C -C–H -C–H 2 − NH NH , the 2 105 2 H Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 the mechanism is still an active area of active research. an area is still mechanism the 3.8 available scheme shownFigure consistent is the general data, with in the Although needed. are data [164,176,177]topology additional the and possible,of models also Alternative endoplasmic are reticulum. the spanning regions transmembrane five has enzyme [175], the and that protein proposed been the has it in regions hydrophobic seven indicates carboxylase the of sequence acid amino The established. firmly been yetnot has carboxylase the oftopology membrane The ulum. membrane-spanning of number a with located in lumenthe domain of endoplasmicthe and a retic- C-terminal in N-terminus the domains protein membrane integral an of suggestive sequence a with protein residue 758-amino-acid unique a is [174].carboxylase cloned The and homogeneity negative the with else interact to allow [172,173]. charge nothing and residue Gla the of formation the allow to removedis proton the when occurs that negative charge concerted mechanism allowsmechanism concerted the Glu deprotonation to followed be directly by CO A process. deprotonation involved the residue is in histidine a studied, is microsomes purified less residue[170,171]. than carboxylase rather whenaffinity-purified that demonstrated been also Ithas lysine a as it haveidentified studies recent more butresidue, cysteine a be to thought initially was suggests that this activity may be as widespread as the carboxylase. The importance of epoxide the carboxylase. importance the activity as may widespread The as be suggests this that in gene VKOR identified the of presence The epoxide. lating circu- of amount the of increase an in results which quinone, the to epoxide K vitamin recycle the ofVKOR to ability the VKOR decreases the with ofwarfarin carboxylase.Interaction the drive to needed is which hydroquinone, K vitamin the generate to VKORC1structure the within residues Cys involvingpaired relay electrical an through form hydronaphthoquinone the to reduced are vitamin K of forms epoxide and quinone VKORC1[183–185].the Both called Da 18,000 of mass animal. anticoagulated of amajority to epoxide an in is approximately 1:10 K-2,3-epoxide ofmin vitamin forms less the to oxidized the increase but can [KO])and the 2,3-epoxide feed can K liver into cycle.this vitamin liver, normal In the ratio of vita- esized esized to be the strong base the that abstracts was hypoth- 3.8). (Figure intermediate This intermediate alkoxide an generates that dioxetanering a of formation the in results group methyl the to adjacent carbon carbonyl naphthoquinone the at Dowd by proposed al. first et that [168,169]is hypothesis O of attack initial an that who suggested the abstract to basic 106 but are excreted in the urine [178]. urine the of50excreted in range Glaexcretionthe adultbut are in is Human metabolized not are residuesthat Gla generates proteins K–dependent vitamin of degradation The t 3.6.3 CO with interact K cycle” 3.9).(Figure K forms of(the vitamin Three quinone [K], the hydronaphthoquinone [KH wasmals key [181,182] to an understanding of of the details what is now referred to as the “Vitamin ani- these liversof in reductase epoxide the of activity the of study the and rats, warfarin-resistant KH epoxidethe to quinone the and eventuallyform of to carboxylasethe vitamin the substrate, vitamin of reduction the prevents reductase the [180].of (VKOR)Blocking reductase epoxide K vitamin the ofcalled inhibition an enzyme the K through action wasofinhibition indirect vitamin warfarin [179]. that suggestedwarfarin This anticoagulant 4-hydroxycoumarin the administered animals in and reduced activelyrecycled, and be the hepatic must ratio carboxylase of the the epoxide by relative generated to that of2,3-epoxide the wasK vitamin found to vitamin be increased the that clear 0.2 approximately only is K vitamin of intake averagedietary day. The each formed is amount similar a that cating Progress in purifying the carboxylase was slow, but the enzyme was eventually purified to near near to slow,wascarboxylaseeventually purified was the enzyme the but purifying in Progress VKOR has been shown to be a three-exon protein containing 163 amino acids with a molecular molecular a with 163 acids amino containing protein three-exon a shown be VKOR to been has Experiments designed Experiments chemical to form identify ofK an intermediate that is vitamin sufficiently 2 . Widespread use as ofrodenticidean anticoagulant warfarin led to of ofthe appearance strains he V i tam 2 . The active-site base that is needed to deprotonate the vitamin K hydroquinone K vitamin the deprotonate to needed is that base active-site The . μ i mol/day, and a mole of vitamin is oxidized for each mole of Gla formed. It is It formed. Gla of mole each for oxidized is vitamin of mole a mol/day, and n γ KE -hydrogen of the glutamyl residue have been a challenge. The most likely most The challenge. a been have residue glutamyl the of -hydrogen p ox i de R eductase γ -methylene hydrogen and leaves that can a carbanion and other insects [186] insects other and Drosophila Handbook of Vitamins Handbook 2 to neutralize the to neutralize μ mol/day,indi- 2 ], 2

Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 prothrombin activity, actually measure the concentration of thrombin that has been generated from from generated been has that ofconcentration activity,the thrombin measure prothrombin actually chromogenic substrates can also be used to assay activity.their These assays, when to assayutilized proteases, serine are factors clotting K–dependent vitamin the As prothrombin. than rather VII tor half-life, shortest assays level itthe one-stage is prothrombin measure often likelythese that ofthe fac- has VII factor as and X, and VII factors and prothrombin levelsof the to responds assay The sue factors. Variations of assaythis have been developed, and reagentcommercial kits are available. of calcium and a lung or extract brain (thromboplastin) phospholipidspreparation to furnish and tis- addition the a “quick plasma in assay time”) called clotting cally after times measures prothrombin (histori- PT recalcified, or time” takes “prothrombin it standard The clot. fibrin time a form to plasma the oxalated or citrated, measure use in currently tests Standard X. factor or IX, factor VII, factor II), (factor prothrombin factors: clotting K–dependent vitamin the of one of concentration plasma the measure to K was vitamin of intake inadequate an define to used method classical The m 3.7.1 3.7 proteins. production important of the these stepin rate-limiting the is carboxylase the of activity the than rather enzyme this by K vitamin reduced of production the forreductase the synthesis K–dependentof proteins is byvitamin illustrated observations [187] that lesssensitive warfarin. to are that reductases quinone NADPH-linked hydronaphthoquinone the or by reductase one to dithiol-driven or form either more by of warfarin-sensitive same NADH hepatic the the or reduced be can vitamin the of form naphthoquinone The dithiol. reduced a by to reduced the quinone form of by the the vitamin enzyme, a VKOR. warfarin-sensitive reaction is This driven F Vitamin K Vitamin I GU

RE He 3.9 a ethodology

lt S S Tissue recycling of vitamin K. Vitamin K epoxide formed in the carboxylation reaction is is reaction carboxylation the in formed epoxide K Vitamin K. vitamin of recycling Tissue h

I m Warfarin pac OH OH ts o R HSH SH HCH CH f COOH ~ Altered Vit NAD(P) 2 O + 2 CO NAD(P)H 2 a min K O O R CH S S ~ COOH CH S 2 t a COOH t u s Warfarin O O HSH SH R O 107 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 markers of vitamin K status, but a clinically significant decrease in PTsin decrease not seen. was significant but aclinically Kstatus, of vitamin markers cies ofK–dependent proteins. vitamin Because they lack complementthe full of Kstatus. vitamin clotting factor assays have value determining little in had [188]. methods byvarious relativeprothrombin oflacksensitivity,oftheir Because historical these 108 shown to alter the displacement of warfarin from its plasma albumin carrier, induce the hepatic the induce carrier, albumin plasma its been from have warfarin drugs of displacement and the variation, alter to this shown of some for responsible be to found been have Drug interactions time. over patient individual an in substantially vary may and individuals between 20-fold as much as by varies warfarin of dose given a by produced effect anticoagulant the of magnitude The residues.Gla of number normal the of portion a or all lacking proteins K–dependent vitamin plasmaof the to secretion the in results warfarin anticoagulant VKOR oral of the by the Inhibition a 3.7.3 approximately 10 containing diets utilizing studies controlled of number a recently, More subjects. these in established clearly was responsive hypoprothrombinemia K vitamin of degree significant intravenously fed patients K givendebilitated synthesis. A vitamin antibiotics intestinal to decrease ments have cited study often [194] An rare. been of starved K requirement investigated vitamin the population. bacterial response [193],coumarin-like which might be a than more presumed influenceimportant onthegut a exerting are they that likely is it and episodes, hypoprothrombinemic of number large a in cated impli- have been cephalosporins third-generation and second- Some hypoprothrombinemia. the to effect was presumed on the alone gut notthat bacteria and may related intake represent low dietary but gut, it the from availability is possiblemenaquinone by caused to cases many be that decreased assumed been usually have episodes extensively[192].reviewed These been have and antibiotics receiving patients in reported been frequently haveevents K–responsivehemorrhagic Vitamin K. vitamin dietary in alterations to response a [191]influence study not does sex or age that indicates [190],K vitamin recent more buta of oral administration to responds that hypoprothrombinemia a A relatively shown been population has to have of olderpercentage high an adult hospital-admitted relatively though problem and, adult population significant presenta the individuals. rare, for some in therefore,occur deficiency do, K vitamin acquired an liver.of small (d)Cases normal and a the intestine, in surface absorptive normal (c)a intestine, the in bile of presence the (b) vitamin, the K deficiency: to prevent basic out the factors pointed needed a vitamin dietcontaining (a) a normal has and areas problem potential reviewedthe O’Reilly [20] has observed. be sometimes can emia K–responsivehypoprothrombin- human vitamin a buthemostasis, normal maintain to needed that excessof in K vitamin of amount an containing diet a consumes normally population human The a 3.7.2 increased. calcium were not However, shown artery of measurements the as carboxylation to coronary decrease ofincreases. MGP intake K vitamin the as decreases form undercarboxylated the of degree the and K, vitamin of intake the with associated is MGP plasma [189] undercarboxylated shown that The need for vitamin. complete carboxylation is notas it as important once was thought. It of has been levels circulating of in alterations of the intake basisof recent onthe subject day-to-day to variation values butare these reflected the vitamin, also is status K Vitamin deficiency. K detect to vitamin used a be also can and developed been have prothrombins “abnormal” these for specific or by are salts that electrophoresis. Antibodies to bind to barium ability their form by in alterations their normal from theyandbeseparated can altered, is acid residues,affinity calcium binding their Human vitamin Human K vitamin deficiencyresults in the secretion into the plasma of carboxylated partially spe- Experimentally induced Experimentally K vitamin deficienciesthat are sufficiently severe toreduce PTmeasure- μ g/daylessorof phylloquinone [80,116,195] sensitiveusingmore have alterations demonstrated dult nt i coagulant V i tam i n KD T hera ef i c p y i ency Handbook of Vitamins Handbook γ -carboxyglutamic -carboxyglutamic Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 Vitamin K Vitamin or if severelyor if out of or even by range subcutaneous slow intravenous of phylloquinone. infusion of >7.0. Overanticoagulation can be brought back to the desired level by loweringdose, the warfarin related to with the fewINR bleeds at a stable of INR <4.0 and a relatively high incidence with INRs ofan INR 2–3 [200]. The most common complication of therapy,anticoagulant bleeding, is directly levels range ofthe in 20%–30%which K–dependentof wouldprocoagulants normal, of be vitamin steady-state achieve to is therapy anticoagulant of goal The sensitivities. thromboplastin in ences ratios PT of interconversion sensitivity for by index,allows differ- use whichofinternational PT) corrects an (patient normal PT/mean INR The results. PT reporting for method standardized a as used now is different (INR) ratio with normalized tested international whenthe problem,To PTs overcomethis thromboplastins. different very yield may patient warfarin-treated a from factors, plasma clotting various of levels depressed to sensitivity their throm- in As activity.widely vary prothrombin reagents of boplastin measure true a than rather status procoagulant combined of is not yet that by clearly amechanism Kstatus defined [199]. vitamin decrease E havedoses. Supplemental of and tiveshown bleeding amounts vitamin been to increase warfarin effec- in variation [197,198]the of mostresponsible forCYP2C9 be P450 to variant the ofappear VKOR1,itself,gene or reductase the of Polymorphisms genetic and important. undoubtedly [196], efficacy also is variability warfarin alter also can absorption or intake K vitamin of gut. Alterations the in warfarin to bind or clearance, warfarin with interfere warfarin, metabolizes P450that fraction of ucOC reported in normal healthy human populations ranges from 40% to 50%. These These 50%. to 40% from ranges populations human healthy normal in reported ucOC of fraction conditions. Gla apatite mostIn under standard sites three carboxylated, species, fully butall are the under- defined des- the for assay chemical [59,115]. status K vitamin by immuno- influenced An be can undercarboxylationextentof the and circulating osteocalcin in individuals within the normal population is not completely the levels adult puberty. of Much at the reach and adults, in than to four- fivefold children in young are higher that concentrations at plasma in circulate protein this of amounts Small health. bone in factor possible a as osteocalcin toward directed been has attention bone, in concentration high ofrelativelyits bone.Because in synthesized be to known all MGP, are S Osteocalcin, protein and 3.7.5 K (phylloquinone) dose of 0.5 1mg.” to asingle, should givenas newborns be intramuscular all to “vitamin that advise [205] Pediatrics ofAcademy American the of [204]. recommendations cancers current other The or leukemia childhood of incidence the and K vitamin intramuscular of use the between correlation a show to failed have studies Subsequent VKDB. late of incidence the in increase an and some countries K in of vitamin a led to switch administration to oral This cancers. childhood certain of incidence increased an with associated was infants to K vitamin of injection 1990s effectiveearly [203] the in for intramuscular preventingsuggested report that A VKDB. late as be not may it VKDB, prevent early to vitamin administration ofparenteral effective as as be to administration appears K oral Although problems. malabsorption intestinal severe with infants [202]or exclusively infants in breastfed predominantly age of weeks 12 and 2 between occurring of K is administration vitamin birth immediately after cure. the standard Late VKDB is a syndrome is low, bleeding is high, and prevention rate from intracranial the mortality by oral or intramuscular none, low clotting factor levels, and a sterile gut all contribute to the disease. Although the incidence K vitamin deficiency.The low Kvitamin content of milk, breastlow transfer placental of phylloqui- [201] neonates human a classic the of example healthy-appearing is in life of week first occurring the (VKDB) during bleeding deficiency K vitamin early or newborn the of disease Hemorrhagic h 3.7.4 The anticoagulant effect of warfarin therapy is monitored by is monitored oftherapy PT, measurement the a measure effect of warfarin anticoagulant The P oss emorrhag i ble γ -carboxylated osteocalcin (ucOC) as that fraction that does not adsorb to hydroxy- to adsorb not does that fraction that (ucOC) as osteocalcin -carboxylated R ole i c

D i n B i sease γ one -carboxylated form of osteocalcin is available, but most studies have studies most but available, is osteocalcin of form -carboxylated

H of

ealth the N ewborn γ -carboxylated -carboxylated 109 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 ucOC and decreased mineralization. ucOC When and mineralization. decreased γ achievemaximal to required is [RDI]) intake daily (~10recommended day per nonecurrent the × maximally to sufficient not is K γ vitamin of intake dietary normal the that established have data 110 both Kboth sexesresponse, andconcentrations rat,vitamin in can thisthe prothrombin castrated unifies of Castration rats. male in produced readily more much are deficiencies nutritional that and ment require- K lowera vitamin had rats female that indicated requirements K vitamin of studies Early newborn. the in hemorrhage K–responsive vitamin a produce [216] to reported been has women pregnant to administration diphenylhydantoin and Phenobarbital quantitate. to difficult been has increased greatly is under germ-free conditions rat [215], the of the significance requirement ofthe K utilization ofgut menaquinones byvitamin humans the that demonstrated easily is it Although o 3.7.7 changes of is not these clearly impact defined. health levels with increased K–dependentis calcification, associated proteins, butthe of coronary vitamin ofcarboxylation of degree the reduce substantially wouldwhich treatment, coumarin chronic that [212–214] studies [130,131]. recent menaquinones indicate that and clear K is It vitamin of intake research has focused on the relationship between various types of aortic calcificationand the dietary under- to menaquinone of lowintake a link to data [211].death cardiovascular and sudden infarction, however,are, calcification, myocardial There no ological study has shown, however, an inverse relationship menaquinone between and aortic dietary slightly lower calcificationaortic in subjectswith a lower Kintake. A vitamin much larger epidemi- and K phylloquinonecalcification [210] vitamin [209] ortotal have intake shown norelationship or action The of the MGP requires calcification. cartilage abnormal by characterized conditionrecessive autosomal rare a syndrome, Keutel of the phenotype the with associated MGP are found the [208] been in mutations Ithas that model a rat valves when in seen MGP carboxylation been has heart was blockedand [129].arteries 8 weeks within [128],ofof birth large the arteries and a rapid calcification theof elastic lamellae of massive calcifications from died animals these that indicated mouseknockoutMGP the of Studies 3.7.6 therapy. any, if rate, this was after observed adult fracture the in decrease found only asmall that [121,122] trials and approach. Recentmeta-analyses nutritional a than rather pharmacological have istherapy 45 mg of standard MK-4 day,The per countries. Asian other Japanosteoporosis in and a for therapy common a is MK-4 with supplementation mineralization, bone to normal for appear needed not be does osteocalcin of carboxylation maximal Although density. mineral bone hip in only onediets, study [207] to the K was found increase added an supplemental as ucOC vitamin in [117–119,207] studies these all olderAlthough adults. loss in ofgression bone reduction a reported clinical controlled [59,114]trials randomized of have series if supplementation slow K conducted been will to ofdetermine vitamin pro- the a recently, More K. vitamin with supplementation after outcomes mixed reported have studies these and risk, fracture hip and density mineral bone with mass. bone decreased than rather mineralization bone utilizing Studies gene [113] osteocalcin the lacking mice transgenic mineralization. haveincreased phenotype decrease the that demonstrated would status K vitamin low that indicate not does but mineralization, bone skeletalinvolved is regulating probablyin osteocalcin, a protein, K–dependent that vitamin suggest data These observed. been has growth longitudinal of cessation and plate rat model [112], bya disorder characterized mineralization complete fusion of proximal tibia growth -carboxylation. At the present time, there is no clear evidence to support a link between increased increased between is no evidencea link clear there -carboxylation. to support present Attime, the phylloqui-mg 1 supplementation with that shown[206] been has it and osteocalcin, -carboxylate There have been numerous observational studies that have examined the association of ucOC ucOC of association the examined have that studies observational numerous been have There P oss ther i ble F R actors ole

i n I V nfluenc ascular γ -carboxylated -carboxylated form, and studies of relationshipthe between aortic i ng C V alc i tam i f γ i -carboxylation of osteocalcin is effectively blocked in a cat i n KS i on γ tatus -carboxylation. Current interest in this area of area this in interest Current -carboxylation. Handbook of Vitamins Handbook Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 function in eukaryotic cells is not cells yet known. eukaryotic in function carrier similar a exerts MK-4 Whether production. ATP normal maintain to carrier electron drial a that is possible numerous are that there but not yet functions.identified Ithas recently been shown [227] none oldin fed havewith rats cognitiveis rats. associated K intake impairments found vitamin that cognitiveinvestigated,lifelonghuman shouldability and studies utilizing lowbe further phylloqui- and status K vitamin between relationship[226], a available data the of basis the [224,225]. K On vitamin dietary in increases similar to response in increase sphingomyelindo and sulfatides brain of activity of keythe sphingolipid enzymes biosynthesis [223]. have studies More recent found that involved be may also interaction. this vitamins in the causative agent [223]. A more recent study [199] suggests that alteration forof these transporters that indications some are there and vitamins, both of degradation similar the to related be to thought been [222].for study has years 50 under interaction been forbasis this The to cause a hemorrhagic episode years ago [221], and the relationship between these two has vitamins addition The E of to the diet vitamin of therapy a anticoagulation was patient reported on coumarin acid. retinoic and acetate levels relativelyretinol ofat lowobserved dietary be can itclear,but not is antagonism K vitamin specific a or lipidabsorption nonpolar effecton general a is this Whether [220].action K vitamin adverselyinfluence to time some for recognized been also has A vitamin vented its absorption, oil and mineral has often been used K–deficientin vitamin diets. High dietary proteins the of synthesis Kmetabolism. involved any to effect on vitamin of than rather rates to related are effects hormonal these that likely is it [219], and K–dependent clotting factors ofof rate the vitamin synthesis destruction the both in and a decrease [218]. microsomes the in precursors mulation of prothrombin in results humans Hypothyroidism in that the influence ofestrogens onrate of synthesis isreflected in highera rate ofsynthesis andaccu- [217].suggests evidenceavailable androgens with The decreased and estrogens with increased be livestock a rations water-solubleusually utilize Commercial assay. preventiveform of menadione, long-term such as MSBC. compound a This in phylloquinone to equal nearly activity shows often factor, butcurative a assay, MK-4probably to isin rate-limiting of itsthe alkylation rate wherethe ineffective rather Itis used. is ofassaythat type the on deal great a depends butthis basis, molar a onphylloquinone effective as as 40% to 20% from be to considered usually is Menadione rations. for nutrition most used K usually studies, in practical whereas are other forms experimental of used vitamin been has Phylloquinone and requirement. used, werethe establish vitamin to employed the were of methods forms different different old, are data the of majority The species. gastric mono- most have, in Deficiencies however, diet. produced the been in vitamin of source a need to requirement. of lowK because increased causeof may activity the the be epoxide reductase studyspecies. A [228]more recent recycling this of in vitamin menaquinones suggests limited that synthesis of ofrelatively chick the the or tract to limited through sit intestinal ofshort rate material deficiencydietary anythan other species.Thishas usuallybeen assumed to be dueto the rapid tran- likely are muchdevelop to more poultry and a symptoms of in chicks, noted wasK first ofvitamin deficiency spontaneous coprophagy.A practice species different which to degree the and bacteria of degrees to the varying which they the large utilize amount ofK bysynthesized vitamin intestinal The establishment K of requirement forvitamin a dietary various species has been difficultbecause a 3.8.1 3.8 Vitamin K Vitamin Although the only known function of vitamin K has been its ability to drive the carboxylase, itcarboxylase, the drive to ability its been has K vitamin of function known only the Although K is Vitamin in present the form mainly in ofthe brain MK-4, and it is in implicated modulating pre- diets in oil mineral of inclusion the that established function K vitamin of studies Early Ruminal microorganisms synthesize large amounts of vitamin K, and ruminants do not appear appear not do ruminants and K, vitamin of amounts large synthesize microorganisms Ruminal

mitochondrial dysfunction be can rescued mitochondrial byDrosophila MK-4, which serves as a mitochon- Vit n a i min K mals R eq u irements α -tocopherol may be be may-tocopherol 111 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 rodents shouldrodents have 750 μ laboratory for diets purified that recommended now[232] Nutrition has of Institute American the levelkg. this Although is sufficientin most did cases, it notprevent signsall ofdeficiency [84], and most species are in the range of 3000 3000 of for range the in Recommendations [229].are species most Sciences of Academy National the by animals laboratory most for recommended been has K these values.considerably A influence of highervitamin an level dietary have of will flora intestinal altering conditions or absorption lipid influencing condition any and nitude of the forrequirement various species. can be requirement byaltered This age, sex, or strain, [231],which have a from tableby presented adapted Griminger been give indication of mag-an the 112 dietary allowance, can be calculated. As sufficient data to determine an EAR are not are the available, EAR an determine to sufficientdata As calculated. be allowance, can dietary recommended the requirements, nutrient indicate to used term historical the EAR, an of mination deter- the allow available data If EAR. an establish to needed data provide the to fail also status K 3.7.5(see Sections health 3.7.6)vascular or and Reports bone vitamin available.implicate in might alterations to that are markers these of basis the on (EAR) requirement average estimated an of able immunoassay. However, no a studies range utilizing of that wouldintakes allow the calculation under- in increases excretionand Gla urinary in decreases in result to conditions controlled under demonstrated been have normal 10%ofof range the in are that K vitamin of Intakes intake. adequate an of indicator circulating As nonexistent. satisfactory a not also itis to previousintakes, dayon dependent very is phylloquinone concentration uncommon are alone intake dietary in changes by PT the in tions deficiency,apparent index referencesetto a adequacy this not used was of value. loquinone is to needed achieve response.this As to there appeared be no significanceclinical ofthis phyl-of mg/day 1 approximately with supplementation that and MGP and osteocalcin circulating maximally to K vitamin sufficient consume individuals any, few, if very that establish to data ample [42].are Sciences of Academy There National the by published havebeen and Medicine of Board/Institute Nutrition and Food the of project comprehen- Intakes Reference the siveofDietary part as 2001 in established were intake K vitamin for values recent most The h 3.8.2 2–200 species, the activities of menadione, MSBC, and phylloquinone are roughly onequal a weight basis. to appears be about as active on a molar basis as phylloquinone in rations, poultry and at least in this Currently, the only indicator of vitamin K status with clinical significance is the PT,altera- and the is significance clinical with status K ofvitamin indicator only Currently,the of range a in falls species most for requirement K vitamin the that indicate data available The Note: Turkey poult Chicken Rat, male Rhesus monkey Pig Dog S K Vitamin Tab μ pecies g of vitamin K per kilogram of body weight per day [220,229,230]. The data in Table[220,229,230]. dayin weight 3.3, per body data of The kilogram per K vitamin of g umans

le 3.3 of equalweightsdifferent formsofthevitaminhasbeenmade. vitamin needed to prevent the development of a deficiency. No correction for differences in potency of amount the as presented are and [231] extensivetable more a from summarized been have Data R γ equirements of Various equirements -carboxylated prothrombin, which can be measured by a commercially avail- commercially a by measured be can which prothrombin, -carboxylated g of phylloquinone added to each kilogram of diet. g of phylloquinone kilogram each to added D aily I ntake (μg/kgperday) 180–270 80–120 11–16 μ 1.25 g/kg of diet, but the rat requirement has been set at 50 at set been has requirement rat the but diet, of g/kg 2 5 S pecies D ietary Concentration (μg/kgdiet) 100–150 1200 530 Handbook of Vitamins Handbook 60 50 60 γ -carboxylate their their -carboxylate μ g/ Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 Vitamin K Vitamin R K Vitamin administered. be shouldalso salts bile function, ary problem, K vitamin can be given orally or parenterally. If given orally to patients with bili- impaired K have been [233,234].reported For treatment of prolonged clotting times when hemorrhage is not a No to attributed hazards the long-term ingestion of elevated amounts of the forms natural of vitamin 3.9 population. general of those the from differ women notdo lactating or of pregnant intakes the data, basisof those the On III. NHANES bythe children, adolescents, and adults are based on the highest median intake for each age group reported phylloquinone the on based content also receive and assume that infants are of milk prophylactichuman forK AIs at birth. vitamin infants of AIs adequate.” be to assumed are that people healthy of apparently groups or by group a ofintake nutrient estimates or approximations determined tally or experimen- observed level on intake based daily average recommended “the as defined is value Table 3.4.The in shown groups age different for (AI) intake adequate the is use in currently RDI bilirubin is extremely toxic to the neonatal brain and has caused death in some instances [233]. some instances in death caused has and is extremely brain toxic neonatal the to bilirubin conjugated in increase marked This kernicterus. and hyperbilirubinemia, hemolyticanemia, cause newborn, groups known ofcompounds these to are react sulfhydryl with various tissues free and to the of disease hemorrhagic the of treatment for prescribed once Although condition. hemorrhagic a for treatment pharmacological a as used be not should but deficiency a developmentofpre- the vent to levelslow at used safely be can compounds These water-solublederivatives. its or dione a before necessary be is apparent. clotting times in may decrease substantial hours of number a and factors, clotting therapy normal Effective of therapy. synthesis of requires route recommended the is injection intramuscular present, is sode epi- hemorrhagic severe a unless and administration, intravenous after noted been have reactions or as an aqueous colloidal solution that can be given or intramuscularly intravenously. Some adverse

e 1. 2. 3. 4. The relative safety of phylloquinone and, presumably, menaquinones does not hold for mena- for hold not does menaquinones presumably, and, phylloquinone of safety relative The f eFF eren

Dam, H.,Cholesterinositoffwechsel inhuhnereiernundhuhnchen.Biochem Z,1929.215:p.475–492. The vitamin A andvitaminDcontentoffishmeal meatmeal.Biochem J,1931.25:p.358–366. McFarlane, W.D., W.R. Graham and F. Richardson, The fat-soluble vitamin requirements of the chick. I. Holst, W.F. andE.R.Halbrook, A “scurvy-like” diseaseinchicks.Science,1933. 77: p.354. Dam, H., The antihaemorrhagicvitaminofthe chick.Biochem, 1935. J29:p.1273–1285. i c cac es y 14- to18-year-old boys andgirls 9- to13-year-old boys andgirls 4- to8-year-old children 1- to3-year-old children 7- to12-month-oldinfants 0- to6-month-oldinfants Population A Tab a Note: 19- to>70-year-old women 19- to>70-year-old men

a I No alterationofintake forpregnancy orlactation. s of Vitamin K s of Vitamin nd H

le 3.4 Dietary referenceintakes [42]. a z a rds o a f P a ha rm ac olo Vitamin K(μg/day) g 1 is available as the pure compound compound pure availablethe is as i ca 120 2.5 2.0 60 55 30 90 75 l D oses o f Vit a min K 113 Downloaded By: 10.3.98.104 At: 10:30 25 Sep 2021; For: 9781466515574, chapter3, 10.1201/b15413-4 114

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