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The Coenzyme Forms of Vitamin B12: To- Ward an Understanding of Their Therapeutic Potential

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The Coenzyme Forms of Vitamin B12: To- Ward an Understanding of Their Therapeutic Potential The Coenzyme Forms of Vitamin B12: To- ward an Understanding of their Therapeutic Potential Gregory Kelly, N.D. Abstract Although cyanocobalamin and hydroxycobalamin are the most commonly encountered supplemental forms of vitamin B12, adenosyl- and methylcobalamin are the primary forms of vitamin B12 in the human body, and are the metabolically active forms required for B12-dependent enzyme function. Evidence indicates these coenzyme forms of vitamin B12, in addition to having a theoretical advantage over other forms of B12, actually do have metabolic and therapeutic applications not shared by the other forms of vitamin B12. This article will provide an overview of the metabolism and function of adenosyl- and methylcobalamin, and will discuss the potential therapeutic relevance of the coenzyme forms of vitamin B12 in a variety of clinical conditions, including anemia, anorexia, cancer, HIV, and liver and sleep disorders. (Alt Med Rev 1997;2(5):459-471) Introduction Cyanocobalamin (CN-Cbl) is the most commonly supplemented form of vitamin B12, but it is present in the body in trace amounts and its biochemical significance remains uncertain. Although the amount of cyanide is considered toxicologically insignificant, humans must re- move and detoxify the cyanide molecule, reduce the cobalamin to its usable +1 oxidation state, and then enzymatically convert the cobalamin into one of two metabolically active coenzyme forms. Nutritional inadequacies, enzyme defects, and pathological changes to tissues can all contribute to a reduced ability of the body to accomplish the synthesis of the active forms of vitamin B12 from CN-Cbl. The two forms of vitamin B12 having activity in B12-dependent enzymes within the human body are adenosylcobalamin (AdeCbl) and methylcobalamin (MetCbl). AdeCbl is occa- sionally referred to as coenzyme B12, cobamamide, cobinamide, or dibencozide. In some bio- chemical or therapeutic situations, the clinical utilization of either AdeCbl or MetCbl (alone or in combination) can produce results not found with the supplementation of either CN-Cbl or hydroxycobalamin (OH-Cbl). Gregory S. Kelly, N.D.—Associate Editor, Alternative Medicine Review; Private Practice, San Diego, CA. Correspondence address: 937 South Coast Highway 101, Suite 205. Encinitas, CA 92024. [email protected] Alternative Medicine Review ◆ Volume 2, Number 6 ◆ 1997 Page 459 Copyright©Copyright©19971997 Thorne Thorne Research, Research, Inc. Inc. All All Rights Rights Reserved. Reserved. No No Reprint Reprint Without Without Written Written Permission Permission Figure 1. Synthesis ofcyanocob coenzyme (lll) alaminforms of B12. NADPH (B3 dependent) In humans, the cobalt in the co- decyanation GSH enzyme forms of vitamin B12 FAD (B2 dependent) exists in a univalent (+1) oxida- tive state, designated as hydroxy cob (lll) alamin cob (lll) alamin cob(I)alamin. Cobalamin mol- ecules can also contain cobalt in NADH reduction FAD or FMN a +3 (cob(III)alamin) or +2 (cob(II)alamin) oxidative state; however, in these forms the co- cob (ll) alamin balt must be reduced prior to hav- ing enzyme activity. SAM The compound most com- monly referred to as vitamin B12 SAH reduction is CN-Cbl; however, this mol- ecule does not occur naturally in methylcob (ll) alamin NADH plants, micro-organisms, or ani- FAD or FMN mal tissues.1 CN-Cbl has a cya- THF homocysteine nide molecule at the metal-car- bon position and its cobalt atom 5MTHF methionine exists at an oxidative state of +3, not the biologically active +1 cob (l) alamin state. In order to be utilized in the body, the cyanide molecule must be removed and eliminated cob (l) alamin through phase II detoxification. ATP It is thought that glutathione (GSH) might be the compound performing the function of adenosylcob (l) alamin decyanation in vivo, since glutathionylcobal-amin (GS-Cbl) has been isolated from mamma- lian tissue.2 If, in fact, GSH is needed as a cofactor to activate CN-Cbl to the Biochemistry, Metabolism, and coenzyme forms of vitamin B12, clinical situ- Enzyme Functions ations characterized by decreased tissue lev- Cobalamin is a very complex mol- els of GSH might be expected to result in a ecule, containing cobalt surrounded by five functional deficiency of vitamin B12, even in nitrogen atoms. Surrounding this central co- the presence of adequate plasma or tissue lev- balt is a corrin ring, which structurally re- els of the cobalamin moiety (typically labs are sembles the porphyrin ring found in hemoglo- looking only for a cobalamin moiety and do bin, the cytochromes, and chlorophyll. The use not differentiate between CN-Cbl and the ac- of cobalt in the coenzyme forms of cobalamin tive forms of vitamin B12). is the only known function of this metal in bio- Humans are incapable of synthesizing logical systems. the corrin ring structure, and so are completely dependent upon dietary sources of vitamin B12. The ultimate source of all vitamin B12 Page 460 Alternative Medicine Review ◆ Volume 2, Number 6 ◆ 1997 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission V itamin B12 occurring in the diet is bacteria, with animal MetCbl’s only known biological func- products providing the majority of the dietary tion in humans is as a cofactor in the enzyme intake. It had been proposed that humans could methionine synthase. The methionine synthase absorb vitamin B12 formed by colonic flora; enzyme is located in the cytosol of cells and however, this appears to be untrue since no participates in the transfer of methyl groups significant amount of cobalamin can be ab- from 5-methyltetrahydrofolate to homocys- sorbed in the colon.1 teine, resulting in the subsequent regeneration/ The optimal absorption of dietary vita- remethylation of methionine. min B12 requires the formation of a complex Pezacka et al have proposed that at between dietary cobalamins and R-proteins, least four steps are required to convert supple- and the secretion, by the stomach parietal cells, mentary CN-Cbl to the coenzyme forms of vi- of intrinsic factor. The cobalamin-R-protein tamin B12. These are: (i) decyanation; (ii) re- complex is digested by pancreatic enzymes in duction of the +3 and +2 forms; (iii) synthesis the small intestine, and the released cobalamin of MetCbl in the cytosol; and (iv) synthesis of molecule binds with intrinsic factor and is ab- AdeCbl in the mitochondria. The initial step sorbed in the distal ileum. Cobalamin is then of decyanation is probably dependent on GSH, detached from intrinsic factor in the enterocyte possibly in combination with NADPH and cells of the small intestine, and is bound to FAD.2 This results in the formation of transcobalamin II for transport into tissues. cob(III)alamin. OH-Cbl is also a cob(III) form Although the basic cobalamin mol- but has an advantage over CN-Cbl since it ecule is only synthesized by micro-organisms, bypasses the need for decyanation. The next all mammalian cells can convert it into the co- step required is the reduction of cob(III)alamin enzymes AdeCbl and MetCbl. OH-Cbl, to cob(II)alamin. This reduction is probably MetCbl, and AdeCbl are the three forms of dependent upon NADH and possibly either cobalamin most frequently isolated from mam- FAD or FMN.2 Once cob(II)alamin is formed, malian tissue. However, only MetCbl and a similar reduction can shunt it into the for- AdeCbl actually function as cofactors in hu- mation of cob(I)alamin and subsequently, with man enzymes. AdeCbl is the major form in ATP, AdeCbl. An alternate pathway can, with cellular tissues, where it is retained in the mi- the donation of a methyl group from S- tochondria. MetCbl predominates in blood adenosylmethionine (SAM), result in the for- plasma and certain other body fluids, such as mation of MetCbl from cob(II)alamin. MetCbl cerebral spinal fluid, and, in cells is found in becomes cob(I)alamin after donating its me- the cytosol.3 thyl group; however, MetCbl can be regener- AdeCbl functions in reactions in which ated, by accepting a methyl group from 5- hydrogen groups and organic groups exchange methyltetrahydrofolate, for reuse in places. In humans, AdeCbl is required for the methionine synthase (see figure 1.). enzyme methylmalonyl-CoA mutase which is Evidence indicates alpha-tocopherol used in the catabolic isomerization of protects against a reduction in AdeCbl in oxi- methylmalonyl-CoA to succinyl-CoA (used in datively stressed cells.4 Experimental evidence the synthesis of porphyrin) and as an interme- suggests alpha-tocopherol might be needed for diate in the degradative pathway for valine, formation of AdeCbl; however, further stud- isoleucine, threonine, methionine, thymine, ies are required to clarify this relationship. If odd-chain fatty acids and cholesterol.1 Defi- alpha-tocopherol is used in the reducing steps, ciencies in this coenzyme form of vitamin B12 a deficiency would be expected to decrease result in increased amounts of methylmalonyl- the formation of both AdeCbl and MetCbl.5 CoA and generally in an increase in glycine. Alternative Medicine Review ◆ Volume 2, Number 6 ◆ 1997 Page 461 Copyright©1997 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission It is important to be aware that nitrous there is some mechanism of absorption inde- oxide inactivates the coenzyme forms of vita- pendent of intrinsic factor.9, 10 It is likely that min B12 by oxidizing cob(I)alamin to either with supra-physiological doses of the coen- cob(II)alamin or cob(III)alamin. Nitrous ox- zyme forms of vitamin B12, some of the ab- ide also interferes with the activity of methio- sorption is also independent of intrinsic fac- nine synthase.6 tor. Absorption Clinical Implications Evidence indicates cobalamin from Anemia: The use of the coenzyme MetCbl is utilized more efficiently than CN- forms of vitamin B12 will be useful in some Cbl to increase the levels of coenzyme forms types of anemia and might offer an advantage of vitamin B12.
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