Pyruvate Kinase: Function, Regulation and Role in Cancer
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Phosphotransferase Activity of Liver Mitochondria (Oxidative Phosphorylation/Adenine Nucleotide Ni-Oxides/Substrate Specificity/In Vivo Phosphorylation) G
Proc. Nat. Acad. Sci. USA Vol. 71, No. 11, pp. 4630-4634, November 1974 Participation of N1-Oxide Derivatives of Adenine Nucleotides in the Phosphotransferase Activity of Liver Mitochondria (oxidative phosphorylation/adenine nucleotide Ni-oxides/substrate specificity/in vivo phosphorylation) G. JEBELEANU, N. G. TY, H. H. MANTSCH*, 0. BARZU, G. NIACt, AND I. ABRUDAN Department of Biochemistry, Medical and Pharmaceutical Institute, Cluj, * Institute of Chemistry, University of Cluj, Cluj, and t Department of Physical Chemistry, University of Craiova, Craiova, Romania Communicated by Henry Lardy, September 3, 1974 ABSTRACT The modified adenine nucleotides ATP- rivatives of adenine nucleotides once produced become "ac- NO, ADP-NO, and AMP-NO were tested as potential tive" components of the mitochondrial or cellular adenylate substrates and/or inhibitors of mitochondrial phospho- transferases. ADP-NO is not recognized by the translocase pool. membrane; system located in the inner mitochondrial AND METHODS however, it is rapidly phosphorylated to ATP-NO in the MATERIALS outer compartment of mitochondria, by way of the The following commercially available chemicals were used: nucleosidediplhosphate kinase (EC 2.7.4.6) reaction, pro-' de- vitded there is sufficient ATP in the mitochondria. AMP- crystalline bovine serum albumin, glucose-6-phosphate NO is not phosphorylated by liver mitochondria to the hydrogenase (Glc-6-P dehydrogenase; EC 1.1.1.49; BDH corresponding nucleoside diphosphate; it cannot serve as Chemicals, Ltd.), yeast hexokinase (EC 2.7.1.1) (Nutritional substrate for adenylate kinase (EC 2.7.4.3). ATP-NO and Biochemicals, Cleveland), (log muscle lactate dehydrogenase ADP-NO, however, are substrates of this enzyme. -
Isozymes of Pyruvate Kinase in Liver and Hepatomas of the Rat1
[CANCER RESEARCH 34, 1439-1446, June 1974] Isozymes of Pyruvate Kinase in Liver and Hepatomas of the Rat1 Francis A. Farina,2 Jennie B. Shatton, Harold P. Morris, and Sidney Weinhouse The Fels Research Institute and the Department of Biochemistry, Temple University School oj Medicine, Philadelphia. Pennsylvania IV140 (F. A. F., J. B. S.. S. W.\, and the Department of Biochemistry. Howard University School of Medicine. Washington. D. C. 20001 [H. P. M .\ SUMMARY 23, 32, 41, 57). These alterations involve the replacement of those isozymes that are under dietary and hormonal control Pyruvate kinase (PK) (EC 2.7.1.40) isozymes were assayed by the host, and that have important metabolic functions in in normal rat liver and a series of transplantable rat the adult differentiated liver by other isozymes which are hepatomas ranging widely in growth rate and degree of normally either low in, or absent from, the adult tissue. As differentiation, with the use of gradient elution by chloride part of an ongoing study of this phenomenon, we have ion from columns of DEAE-cellulose. In agreement with examined the alteration of PK3 (EC 2.7.1.40) isozymes in other studies, three noninterconvertible forms were found in the Morris hepatomas (30. 31), a series of chemically rat tissues: isozyme I, the major form in adult rat liver: induced, transplantable rat hepatomas ranging widely in isozyme II, the sole form in heart and skeletal muscle: and growth rate and degree of differentiation. This enzyme isozyme III, the sole form in poorly differentiated hepato occupies a key position in the metabolism of cells and, as we mas, the major form in normal kidney and lung, and the pointed out previously (27, 28. -
Prevalence of Pyruvate Kinase Deficiency
P3513 Prevalence of Red Cell Pyruvate Kinase Deficiency: A Systematic Literature Review Mike Storm1, Matthew H Secrest2*, Courtney Carrington2, Deb Casso2, Keely Gilroy1, Leanne Pladson1, Audra N Boscoe1 1Agios Pharmaceuticals Inc., Cambridge, MA, USA; 2IQVIA Epidemiology & Drug Safety, Seattle, WA and Cambridge, MA, USA; *Affiliation at the time research was conducted BACKGROUND METHODS (continued) RESULTS (continued) RESULTS (continued) • Pyruvate Kinase (PK) deficiency is a rare congenital hemolytic anemia Exclusion Criteria The remaining 34 studies were grouped based on methods and study Among these 4 studies, an important distinction was made between studies characterized by diminished activity of the PK enzyme in red blood population (Table 1). reporting diagnosed prevalence (n=3) and overall disease prevalence cells (RBC).1 • Non-human studies; (diagnosed and undiagnosed PK deficiency; n=1). Table 1. Distribution of extracted studies by type of study (n=34) • Low PK enzyme activity can lead to lifelong chronic hemolysis with • Publications that were not the primary report of the data • Two studies estimated diagnosed PK deficiency prevalence as 3.2 per associated symptoms and complications such as anemia, jaundice, (e.g., literature reviews); Type of study Number million4 and 8.5 per million5 by identifying diagnosed PK deficiency cases of studies gallstones, splenectomy and associated thrombosis, iron overload, and • Studies of PK deficiency prevalence/incidence conducted within a source from source populations of known size. liver cirrhosis.2 Population-based prevalence 2 population of patients with symptoms of PK deficiency such as anemia • We estimated the prevalence of diagnosed PK deficiency in a general • PK deficiency is caused by compound heterozygosity or homozygosity for or jaundice; Molecular PKLR screening in a general population 5 population to be 6.5 per million6 using data from another high-quality study 3 one or more of the >300 known mutations to the PKLR gene. -
Table S1. List of Oligonucleotide Primers Used
Table S1. List of oligonucleotide primers used. Cla4 LF-5' GTAGGATCCGCTCTGTCAAGCCTCCGACC M629Arev CCTCCCTCCATGTACTCcgcGATGACCCAgAGCTCGTTG M629Afwd CAACGAGCTcTGGGTCATCgcgGAGTACATGGAGGGAGG LF-3' GTAGGCCATCTAGGCCGCAATCTCGTCAAGTAAAGTCG RF-5' GTAGGCCTGAGTGGCCCGAGATTGCAACGTGTAACC RF-3' GTAGGATCCCGTACGCTGCGATCGCTTGC Ukc1 LF-5' GCAATATTATGTCTACTTTGAGCG M398Arev CCGCCGGGCAAgAAtTCcgcGAGAAGGTACAGATACGc M398Afwd gCGTATCTGTACCTTCTCgcgGAaTTcTTGCCCGGCGG LF-3' GAGGCCATCTAGGCCATTTACGATGGCAGACAAAGG RF-5' GTGGCCTGAGTGGCCATTGGTTTGGGCGAATGGC RF-3' GCAATATTCGTACGTCAACAGCGCG Nrc2 LF-5' GCAATATTTCGAAAAGGGTCGTTCC M454Grev GCCACCCATGCAGTAcTCgccGCAGAGGTAGAGGTAATC M454Gfwd GATTACCTCTACCTCTGCggcGAgTACTGCATGGGTGGC LF-3' GAGGCCATCTAGGCCGACGAGTGAAGCTTTCGAGCG RF-5' GAGGCCTGAGTGGCCTAAGCATCTTGGCTTCTGC RF-3' GCAATATTCGGTCAACGCTTTTCAGATACC Ipl1 LF-5' GTCAATATTCTACTTTGTGAAGACGCTGC M629Arev GCTCCCCACGACCAGCgAATTCGATagcGAGGAAGACTCGGCCCTCATC M629Afwd GATGAGGGCCGAGTCTTCCTCgctATCGAATTcGCTGGTCGTGGGGAGC LF-3' TGAGGCCATCTAGGCCGGTGCCTTAGATTCCGTATAGC RF-5' CATGGCCTGAGTGGCCGATTCTTCTTCTGTCATCGAC RF-3' GACAATATTGCTGACCTTGTCTACTTGG Ire1 LF-5' GCAATATTAAAGCACAACTCAACGC D1014Arev CCGTAGCCAAGCACCTCGgCCGAtATcGTGAGCGAAG D1014Afwd CTTCGCTCACgATaTCGGcCGAGGTGCTTGGCTACGG LF-3' GAGGCCATCTAGGCCAACTGGGCAAAGGAGATGGA RF-5' GAGGCCTGAGTGGCCGTGCGCCTGTGTATCTCTTTG RF-3' GCAATATTGGCCATCTGAGGGCTGAC Kin28 LF-5' GACAATATTCATCTTTCACCCTTCCAAAG L94Arev TGATGAGTGCTTCTAGATTGGTGTCggcGAAcTCgAGCACCAGGTTG L94Afwd CAACCTGGTGCTcGAgTTCgccGACACCAATCTAGAAGCACTCATCA LF-3' TGAGGCCATCTAGGCCCACAGAGATCCGCTTTAATGC RF-5' CATGGCCTGAGTGGCCAGGGCTAGTACGACCTCG -
Phosphoenolpyruvate-Dependent Phosphotransferase System in Lactobacillus Casei BRUCE M
JOURNAL OF BACTERIOLOGY, June 1983, p. 1204-1214 Vol. 154, No. 3 0021-9193/83/061204-11$02.00/0 Copyright C 1983, American Society for Microbiology Regulation and Characterization of the Galactose- Phosphoenolpyruvate-Dependent Phosphotransferase System in Lactobacillus casei BRUCE M. CHASSY* AND JOHN THOMPSON Microbiology Section, Laboratory of Microbiology and Immunology, National Institute of Dental Research, Bethesda, Maryland 20205 Received 8 November 1982/Accepted 5 March 1983 Cells ofLactobacillus casei grown in media containing galactose or a metaboliz- able ,-galactoside (lactose, lactulose, or arabinosyl-P-D-galactoside) were in- duced for a galactose-phosphoenolpyruvate-dependent phosphotransferase sys- tem (gal-PTS). This high-affinity system (Km for galactose, 11 ,uM) was inducible in eight strains examined, which were representative of all five subspecies of L. casei. The gal-PTS was also induced in strains defective in glucose- and lactose- phosphoenolpyruvate-dependent phosphotransferase systems during growth on galactose. Galactose 6-phosphate appeared to be the intracellular inducer of the gal-PTS. The gal-PTS was quite specific for D-galactose, and neither glucose, lactose, nor a variety of structural analogs of galactose caused significant inhibition of phosphotransferase system-mediated galactose transport in intact cells. The phosphoenolpyruvate-dependent phosphorylation of galactose in vitro required specific membrane and cytoplasmic components (including enzyme Illgal), which were induced only by growth of the cells on galactose or ,B- galactosides. Extracts prepared from such cells also contained an ATP-dependent galactokinase which converted galactose to galactose 1-phosphate. Our results demonstrate the separate identities of the gal-PTS and the lactose-phosphoenol- pyruvate-dependent phosphotransferase system in L. -
Pyruvate Kinase, Rbc
Lab Dept: Chemistry Test Name: PYRUVATE KINASE, RBC General Information Lab Order Codes: PYKI Synonyms: Pyruvate Kinase, Erythrocytes CPT Codes: 84220 – Pyruvate kinase Test Includes: Pyruvate kinase RBC level reported in U/g Hb. Logistics Test Indications: Useful for the workup of cases of nonspherocytic hemolytic anemia, for a family workup to determine inheritance pattern (pyruvate kinase deficiency is autosomal recessive), and for genetic counseling. Lab Testing Sections: Chemistry - Sendouts Referred to: Mayo Medical Laboratories (MML Test: PK) Phone Numbers: MIN Lab: 612-813-6280 STP Lab: 651-220-6550 Test Availability: Daily, 24 hours Turnaround Time: 1 - 4 days, test set up Monday - Saturday Special Instructions: N/A Specimen Specimen Type: Whole blood Container: Yellow top (ACD- Solution B) tube Alternate tube: Lavender (EDTA) top tube Draw Volume: 6 mL (Minimum: 1 mL) blood Processed Volume: Same as Draw Volume Collection: Routine blood collection Special Processing: Lab Staff: Do Not centrifuge. Send whole blood refrigerated in original collection container. Do Not transfer blood to other containers. Store and ship at refrigerated temperatures. Forward promptly. Patient Preparation: None Sample Rejection: Specimen cannot be frozen; mislabeled or unlabeled specimens; gross hemolysis Interpretive Reference Range: ≥12 months: 6.7 – 14.3 U/g Hb Reference values have not been established for patients <12 months of age. Interpretation: Most hemolytic anemias due to pyruvate kinase (PK) deficiency are associated with activity levels less than 40% of mean normal. However, some patients with clinically significant hemolysis can have normal or only mildly decreased PK enzyme activity, which paradoxically may occur in individuals with most severe symptoms. -
Determination of Hexokinase and Other Enzymes Which Possibly Phosphorylate Fructose in Neurospora Crassa
Fungal Genetics Reports Volume 8 Article 23 Determination of hexokinase and other enzymes which possibly phosphorylate fructose in Neurospora crassa W. Klingmuller H. G. Truper Follow this and additional works at: https://newprairiepress.org/fgr This work is licensed under a Creative Commons Attribution-Share Alike 4.0 License. Recommended Citation Klingmuller, W., and H.G. Truper (1965) "Determination of hexokinase and other enzymes which possibly phosphorylate fructose in Neurospora crassa," Fungal Genetics Reports: Vol. 8, Article 23. https://doi.org/ 10.4148/1941-4765.2129 This Technical Note is brought to you for free and open access by New Prairie Press. It has been accepted for inclusion in Fungal Genetics Reports by an authorized administrator of New Prairie Press. For more information, please contact [email protected]. Determination of hexokinase and other enzymes which possibly phosphorylate fructose in Neurospora crassa Abstract Determination of hexokinase and other enzymes which possibly phosphorylate fructose in Neurospora crassa This technical note is available in Fungal Genetics Reports: https://newprairiepress.org/fgr/vol8/iss1/23 silky sheen is usually observed when CI suspension of the crystals is agitated; the silky appearance is usually IX)+ present on initial crystallization. It is apparent that an enormous number of variations is possible in carrying out the described procedure. It is therefore of in- terest that each of the twelve systems with which we hove tried this method has allowed crystallization without recourse to changes in pH,temperotwe or other conditions except for the inclusion of a mercaptan where warranted. Ox experience at this time in- cludes dehydrogemses, decarboxylases, transferases and protein hornwnes and involves proteins usucllly sensitive to room tempero- tire, proteins with high and low polysoccharide content and complexes of more than one protein. -
Isozymes of Human Phosphofructokinase
Proc. Nat{. Acad. Sci. USA Vol. 77, No. 1, pp. 62-66, January 1980 Biochemistry Isozymes of human phosphofructokinase: Identification and subunit structural characterization of a new system (hemolytic anemia/myopathy/in vitro protein hybridization/column chromatography) SHOBHANA VORA*, CAROL SEAMAN*, SUSAN DURHAM*, AND SERGIO PIOMELLI* Division of Pediatric Hematology, New York University School of Medicine, 550 First Avenue, New York, New York 10016 Communicated by Saul Krugman, July 13, 1979 ABSTRACT The existence of a five-membered isozyme The clinical effects of the enzymatic defect consisted of system for human phosphofructokinase (PFK; ATP:D-fructose- gen- 6-phosphate 1-phosphotransferase, EC 2.7.1.11) has been dem- eralized muscle weakness and compensated hemolysis. The onstrated. These multimolecular forms result from the random differential tissue involvement led to the hypothesis that the polymerization of two distinct subunits, M (muscle type) and erythrocyte isozyme is composed of two types of subunits, one L (liver type), to form all possible tetrameters-i.e., M4, M3L, of which is the sole subunit present in muscle PFK (9, 10). The M2L4, ML3, and L4. Partially purified muscle and liver PFKs proposed structural heterogeneity of erythrocyte PFK protein were hybridized by dissociation at low pH and then recombi- was nation at neutrality. Three hybrid species were generated in supported by immunochemical neutralization experiments addition to the two parental isozymes, to yield an entire five- (11, 12). Karadsheh et al. (13) and Kaur and Layzer (14) have membered set. The various species could be consistently and recently presented data to support the suggested hybrid reproducibly separated from one another by DEAE-Sephadex structure for erythrocyte PFK. -
Inhibition of Spinach Phosphoribulokinase by DL-Glyceraldehyde by ANTONI R
Biochem. J. (1976) 153, 613-619 613 Printed in Great Britain Inhibition of Spinach Phosphoribulokinase by DL-Glyceraldehyde By ANTONI R. SLABAS and DAVID A. WALKER Department ofBotany, University ofSheffield, Sheffield S1O 2TN, U.K. (Received 10 September 1975) Spinach chloroplast phosphoribulokinase is inhibited by DL-glyceraldehyde. The in- hibition is non-competitive with respect to ribulose 5-phosphate (Ki 19mM) and ATP (Ki 20mM). The inhibition is discussed in relation to a previously reported inhibition of CO2 assimilation in intact and envelope-free chloroplasts by DL-glyceraldehyde. It is concluded that the inhibition of phosphoribulokinase is insufficient to account for the inhibition, by DL-glyceraldehyde, of 02 evolution with ribose 5-phosphate as substrate and that a further site of inhibition is also present in this system. DL-Glyceraldehyde inhibits photosynthetic carbon glycylglycine buffer, pH7.4, in a total volume of assiniilation by intact chloroplasts and by the re- 13 ml. The reaction was terminated by the addition constituted chloroplast system (Stokes & Walker, of 2ml of 50 % (w/v) trichloroacetic acid and the pH 1972). The inhibition is most pronounced with intact was adjusted to pH8.0 with KOH. After the addition chloroplasts, a concentration of 1OmM being sufficient of Sml of 1.OM-barium acetate the solution was to suppress 02 evolution completely. It is important centrifuged and the precipitate discarded after because DL-glyceraldehyde is the only known inhibi- washing with Sml of water. Cold ethanol (4vol.) was tor of photosynthesis that is entirely without detect- added to the combined supernatants (total volume able effect on photophosphorylation or photo- 25.4ml); the new precipitate was recovered by synthetic electron transport. -
Structure-Function Studies of Enzymes from Ribose Metabolism
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 939 Structure-Function Studies of Enzymes from Ribose Metabolism BY C. EVALENA ANDERSSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2004 !"" #$"" % & % % ' ( ) * + &( , +( !""( - . - % + / % 0 ( , ( 1#1( ( ( 2-3 1. 45 ." 2 * & & * % * &( , % . * % % ( ) % / ( 0 6 / % ,)' & % % & ( )* % 6 % 6 * ( 0 6 * * % ( - % & 7 % & % & && ( ' && ,)' % /( 2 8 * ,)' & ,'.'' ( ) * % / % * 6 & & / 6 ( 0 . . . ( - * & * % %% & ( 9 * 6 / %% % ( -: % & * . & . , /( , & % * /( ) % / % & % ( ! 6 . . & / 6 % " # $ % # %& '()# %$# # *+',-. # ; ( + , !"" 2--3 ".!#!< 2-3 1. 45 ." $ $$$ .#111 = $>> (6(> ? @ $ $$$ .#111A List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals: I Andersson, C. E. & Mowbray, S. L. (2002). Activation of ribokinase by monovalent cations. J. Mol. Biol. 315, 409-19 II Zhang, R., Andersson, C. E., Savchenko, -
The Phorbol Ester-Dependent Activator of the Mitogen-Activated Protein
Proc. Nat!. Acad. Sci. USA Vol. 89, pp. 5221-5225, June 1992 Biochemistry The phorbol ester-dependent activator of the mitogen-activated protein kinase p42maPk is a kinase with specificity for the threonine and tyrosine regulatory sites (phosphatase 2A/casein kinase lI/pp6O0) ANTHONY ROSSOMANDOt, JIE WUt§, MICHAEL J. WEBERt, AND THOMAS W. STURGILLt§¶ Departments of :Internal Medicine, tMicrobiology, and §Pharmacology, University of Virginia, Charlottesville, VA 22908 Communicated by Stanley Cohen, March 10, 1992 ABSTRACT Mitogen-activated protein kinases (MAP ki- and peptide mapping studies, which identified the site of nases) are activated by dual tyrosine and threonine phospho- intramolecular tyrosine phosphorylation as Tyr-185, the reg- rylations in response to various stimuli, including phorbol ulatory tyrosine site, and excluded Thr-183 as a site of esters. To define the mechanism of activation, recombinant significant phosphorylation in recombinant p42maPk (ref. 8 wild-type 42-kDa MAP kinase (p42nuaPk) and a kinase-defective and unpublished data). Endogenous phosphorylation and mutant of p42maPk (K52R) were used to assay both activator activation of MAP kinase also occur upon incubation of activity for p42aPk and kinase activity toward K52R in stim- immunoprecipitates of p42maPk/p44maPk from mammalian ulated EL4.112 mouse thymoma cells. Phorbol 12,13- cells together with ATP/Mg (10). However, coprecipitation dibutyrate (10 min, 650 nM) stimulated a single peak of MAP of activating factor(s) cannot be excluded in this case. Thus, kinase activator that was coeluted from Mono Q at pH 7.5 and plausible mechanisms for activation include enhancement of 8.9 with K52R kinase activity. Both activities were inactivated autophosphorylation at one or both sites in addition to by the serine/threonine-specific phosphatase 2A but not by the phosphorylation by a Thr-183 and/or Tyr-185 kinase(s), and tyrosine-specific phosphatase CD45. -
Swiveling Domain Mechanism in Pyruvate Phosphate Dikinase†,‡ Kap Lim,§ Randy J
Biochemistry 2007, 46, 14845-14853 14845 Swiveling Domain Mechanism in Pyruvate Phosphate Dikinase†,‡ Kap Lim,§ Randy J. Read,| Celia C. H. Chen,§ Aleksandra Tempczyk,§ Min Wei,⊥ Dongmei Ye,⊥ Chun Wu,⊥ Debra Dunaway-Mariano,⊥ and Osnat Herzberg*,§ Center for AdVanced Research in Biotechnology, UniVersity of Maryland Biotechnology Institute, RockVille, Maryland 20850, Department of Haematology, Cambridge Institute for Medical Research, UniVersity of Cambridge, Cambridge, United Kingdom, and Department of Chemistry, UniVersity of New Mexico, Albuquerque, New Mexico ReceiVed September 10, 2007; ReVised Manuscript ReceiVed October 17, 2007 ABSTRACT: Pyruvate phosphate dikinase (PPDK) catalyzes the reversible conversion of phosphoenolpyruvate (PEP), AMP, and Pi to pyruvate and ATP. The enzyme contains two remotely located reaction centers: the nucleotide partial reaction takes place at the N-terminal domain, and the PEP/pyruvate partial reaction takes place at the C-terminal domain. A central domain, tethered to the N- and C-terminal domains by two closely associated linkers, contains a phosphorylatable histidine residue (His455). The molecular architecture suggests a swiveling domain mechanism that shuttles a phosphoryl group between the two reaction centers. In an early structure of PPDK from Clostridium symbiosum, the His445-containing domain (His domain) was positioned close to the nucleotide binding domain and did not contact the PEP/pyruvate- binding domain. Here, we present the crystal structure of a second conformational state of C. symbiosum PPDK with the His domain adjacent to the PEP-binding domain. The structure was obtained by producing a three-residue mutant protein (R219E/E271R/S262D) that introduces repulsion between the His and nucleotide-binding domains but preserves viable interactions with the PEP/pyruvate-binding domain.