Metabolism

BI2 enters the cell fully oxidized to eoh( lll)alamin. Before newly absorbed B12 can attach to an enzyme, it must be reduced lo cob(l)alamin. An as vet uncharacterized enzyme is thought to reduce coh(IIl)alamin to cobtll)alamin. Methionine synthase reductase (EC2.LI.I35, contains FMN and FAD) might be the enzyme that reduces cob(ll)alamin in a separate reaction to the mctabolically active form, cob(I)alamin. The most common inborn error of B12 metabolism, cbl C". appears to interfere with this step. A thiolatocobalaniin. possibly giutitthiony I -coba I am in. may be an intermediate of cobalamin prosthetic group synthesis (Pczaeka et at.. 1990).

The other biologically active form of B12 is 5'-deoxyadenosy I-cobalamin, Prior to its synthesis in mitochondria it has to cross the mitochondrial membrane by an unknown mechanism. Depending on the form that is transported, it also has to be reduced to cob(l)alamin in two NADH-dependent steps. A series of flavoproteins in conjunction with FAD and l:MN was shown to mediate these reductions in a bacterial model system (l onseea and l.sealante-Semerena. 21)01), The corresponding human enzymes have not yet been identified. Aquacob(l)alamin adenosv I transferase

Cytosol

cO?3

5-Methyl-THF-homocysteine-S-melhyitranst (cobpjalamin)

Methylcob(lll) alamin

5-methyl-THF

5-Methyl-THF-homocysteine-S-melhyitranst (cobpjalamin)

5-Methyl-THF homocysteine-S-methyltranst -cob[l]alamin

Methylcob(lll) alamin

Aquacob(ll()alamin

cO?3

5 - Methyl-THF-homocysteine-S-methyllranst. (cob(llalamin)

Aquacob(ll()alamin

5 - Methyl-THF-homocysteine-S-methyllranst. (cob(llalamin)

5-Methyl-THF homocysteine-S-methyltranst -cob[l]alamin

Cob(t)alamin

llavoprotein

Aquacob(lll)alamin

Cob(ll)atamin

llavoprotein

Aquacob(lll)alamin

Mitochondria

Cob(ll)atamin

Cob(l)alamin

Aquacob(Ualamin adenosyit ranslerase (magnesium?)

Methylmalonyl-CoA

mutase (5-deoxyadenosyl-cob(llt)atamin)

5-Deoxyadenosyl-cob(ltl)alamin figure 10.36 Metabolic activation ofvitamin ft I 2

(EC2.5.1.17; probably magnesium-dependent) transfers the adenosyl group from ATP to HI2. releasing phosphate and pyrophosphate (Fonscca and Escalantc-Semerena, 2001). Sinee this enzyme has been characterized only in microorganisms so far. considerable uncertainties about its characteristics remain. 5' - Dcoxy adertosy Icoba I am i n appears to be preferentially retained in mitochondria, but the exact mechanism is not well understood nor is it known how B12 is released again.

Just as the import of B 12 into mitochondria, the mechanism of its export remains uncertain.

Storage

The main storage form of B12 is 5'-deoxy adenosy 1 cobalamin in mitochondria. Liver may contain 2 5mg BI2 in replete people. About 0.1?» of the body's B12 stores are turned o\ er per day. There is a lack of information on the processes that govern mobilization of stored 5'-deo\yadenosylcobalamin.

Exposure to nitrous oxide (during anesthesia or as substance abuse) can deplete BI2 stores in people with mild deficiency (Carrael, 2000: Marie el a!.. 2000). However, not all studies found a significant effect of nitrous oxide anesthesia on B12 stores (Deleu el ul., 2000).

Excretion

Bile: Significant amounts of cobalamin and related compounds are secreted into bite. Since cobalamin is absorbed from the distal small intestine, extensive cycling between intestinal absorption and hepatic secretion takes place. The entcrohepatic cycling effectively removes non-cobalamin corrinoids from the body, because they are not reabsorbed well, while cobalamin is recovered with very high clliciency. Kidneys The transcobalamin-11 B12 complex, which is slightly over 50 kD in size, is filtered by the renal glomeruli. In the proximal tubules the complex is then taken up by the amply expressed endocytic receptor megalin (Nielsen ei ul., 2001). An alternative mechanism for B12 recovery uses intrinsic factor, which is produced locally in the kidney and secreted by the proximal tubuii. Any free BI2 in the primary filtrate can thus be complexed and taken up via cubilin, the intrinsic factor'B12 receptor. Megalin and cubilin then cooperatively target the complexes towards lysosomes. Thus, the mechanism of cellular uptake and transport across the basolateral membrane is the same as in the dislal ileum. Under most normal circumstances the capacity for reabsorption is not exceeded by the amount entering the proximal tubules, and very little, if any, BI2 is lost into urine.

Regulation

Growth hormone increases secretion of salivary haptocorrin and of gastric intrinsic factor (Lobie and Waters, 1907),

Reabsorption of B12 from proximal renal tubules plays an important role in the regulation of B12 homeostasis, but the involved mechanisms arc not yet fully understood (Nielsen etal.. 2001),

Function

Homocysteine remethylation: S*Adc nosy] methionine (SAM) is the main methyl-group donor for methylations and other one-carbon transfer reactions. The product of this reaction, S-adcnosy ¡homocysteine, can he remethylatcd to the SAM precursor methionine by 5-methyltetrahydrofolate-homocystcine S-methyl transferase (MTR: EC2.Lt.13). The reaction is initiated by the transfer of a methyl group from 5-methyItetrahydrofolate to the prosthetic group of the enzyme, cobl I lalamin, The methyl group linked to cob(UI)alamin is then transferred to S-adenosy(homocysteine.

The cob(I)alamin prosthetic group of MTR is easily oxidized and a small percentage is converted non-enzymieally into the non-reactive cob(ll)alamin form. A FAD- and FMN-dependent enzyme, methionine synthase reductase (EC2.1.I.I35), can revert the oxidized form to its active cobiUalaniin form by reductive ruethylation (Leclerc et u/.. 1498). SAM serves as the methyl-group donor and cytochrome b5 provides the reducing potential. Cytochrome b5 is regenerated by NADPH-dependent cytochrome P450 reductase (ECl.6.2.4). another enzyme with both FAD and FMN as prosthetic groups (Chen and Banerjee, 1998). Inhalation of nitrous oxide irreversibly inactivates MTR (Hornet-/«/.. 1989; Riedel et al., 1999).

It has been suggested that infertility and recurrent fetal loss is due to poor B12 status in some cases. The underlying cause might be hypercoagulation related to elevated homocystein levels (Bennett. 2001).

Prapionvl'CoA metabolism As a result of the breakdown of L-mcthioninc. I.-valine. L-threoninc. the cholesterol side-chain, and of fatty acids with an odd number of carbons, propionyl-CoA is generated. The final step of propionyl-CoA conversion to succinyl-CoA is facilitated by methylmalonyl-CoA mutase (ECS.4.99.2). This enzyme contains 5'-deoxyadenosy Icobal am in as a prosthetic group. Leucine metabolism: It has been reported that a small percentage of L-leueine is metabolized via an alternative beta-keto acid pathway distinct from the prevalent of alpha-keto pathway (Poston, 1984: Ward et uL, 1988). Another investigator did not detect such activity (Aberhart, 1988). The first step is catalyzed by L-beta-leucine aminomutase (EC5.4.3.7) which requires 5'-deoxyadenosy(cobalamin. Subsequent reactions then convert hcta-leueine to beta-kctoisocaproic acid, ligate this intermediate with coenzyme A. and finally generate the valine metabolite isobutvryl-CoA. Since all of these reactions are reversible, the importance of this pathway may be as much L-lcucme synthesis as catabolism. Significant activity is present in testes, where about a third of L-leueine metabolism proceeds v ia this pathway. In all other investigated tissues the beta-keto pathway accounts for less than 5% of L-leucine metabolism. Cyanide antidote: Aquacobalamin readily binds free cyanide and thus is an effectiv e and relatively safe antidote against cyanide poisoning (Sauer and Keim, 2001).

References

Aberhart DJ. Separation by high-performance liquid chromatography of alpha- and beta-amino acids; application to assays of lysine 2.3-aminomutase and leucine 2.3-amino-mutase. Ami Bhchem 1988:169:350-5 Andres E. Kurtz JH. Pcrrin AE. Maloisel F, Demangcat C. (ioichot B. Schlienger JL. Oral cobalam in therapy for the treatment of patients with food-cobalamin malabsorption. 4m J Med 201)1 :l 11:126 9 Bennett M. Vitamin 1312 deficiency, infertility and recurrent fetal loss.,/ Reptvd Med 20Ol;46:209 12

rinse S, Seel ha ram S, Dohms NM, Seeiharam Ii. Bipolar functional expression of transcobaiamin II receptor in human intestinal epithelial Caco-2 cells../ Biol Chem 1997;272:3538-43

Carmel R, Cobalamin, ihe stomach, and aging. Am d (Vi« Y«rr 1997;66:750 9 Carrnel R. ( urrent concepts in cobalamin deficiency. Inn Rev Med 2000:51:357 75 Chen /. Banetjee R. Puritication of soluble cytochrome l>5 as a component of the reductive activation of porcine methionine synthase.,/ Biol Chem 1998:273:26248 -55 Christensen I L Bim H. Megalin and ctibilm: synergistic endocytic receptors in renal proximal tubule. Am./ Physiol Rend Physiol 2001 ;280:F562 F573 Deleu I). Louon A. Sivagnanam S, Sundaram K. Okereke P. Gravell D. Al-Salmy IIS. ■\l Bahrani I. Nam D. Knox-MacAulay 11. Hanssens Y. Long-term effects of nitrous oxide anaesthesia on laboratory and clinical parameters in elderly Omani patients: a randomized double-blind study. J Clin Pharm Titer 2009:25:271 7 Fonseca MV. Escalante-Semerena JC. An in vitro reducing system for the enzymic conversion ofcobalamine to adenosylcobalamin../Biol Chem 2001:276:32101-8 Food and Nutrition Board Institute of Medicine. Dietary Reference Intakes for thiamin, riboflavin, niacin, vitamin B6. folate, vitamin B12. pantothenic acid biotin. and choline. National Academy Press, Washington. DC. 1998. pp.306- 56 Force RW, Nahata MC. LITecl of histamine H2-rcceptor antagonists on vitamin BI2

absorption, Ann Pharmaeoiher 1992;26:1283-6 Hörne DW. Patterson D. Cook RJ. Effect of nitrous oxide inactivation of vitamin BI2-dependent methionine synthetase on the subcellular distribution of folate coenzymes in rat liver. Art h Biochem Biophys 1989:270:729 33 KJttang E. Aadland E, Schjonshy H. Lffcct of omeprazole on the secretion of intrinsic factor, gastric acid and pepsin in man. Gut 1985:26:594 K ko/yraki R. Kristiansen M, Silahtaroglu A. Hansen C, Jacobsen C, Tommerup N, Verroust PJ, Moestrup SK. The human intrinsic factor-vitamin BI2 receptor, cubitin: molecular character /at ion and chromosomal mapping of the gene to 10p w ithin the autosomal reccssive megaloblastic anemia (MGA11 region. Blood 1998;91:3593 6t)0 Kozyraki R, Fyfe J. kristiansen M. Gerdes C, Jacobsen C, Cui S, Christensen EI, Aminolf M. de la Chapelle A. krähe R. Verroust PJ, Moestrup Sk. The intrinsic factor-vitamin B12 receptor, cubilin. is a high-affinity apolipoprotein A-l receptor facilitating endocytosis of high-density lipoprotein. Nature Med 1999;5:656 61 Leclerc D. Wilson A, Dumas R. Gafuik C. Song O, Watkins D. Heng HI Ii J. Rommens JM, Scherer SW. Rosenblatt DS, Gravel RA. Cloning and mappine of a cDN \ for methionine synthase reductase, a flavoprotein defective in patients with homocystin-uria. Pme Nat! had Set USA I998;95;3059 64 Lobie PI:. Waters MJ. Growth hormone (OH) regulation of submandibular gland structure and function in the GH-de lie lent rat: upreyulation of haplocorrin. ./ Endocrinol 1997:154:459-66

Marie RM. Le Biez L. Busson I'. Schacffcr S. Boiteau L, Dupuy B. Viader F, Nitrous oxide anesthesia-associated myelopathy Arch \enrol 2000;57;380 2 Miyamoto L. Waianabe F. Lbara S, Takenaka S. Takenaka H, Yantaguchi Y. Tanaka N, Inui 11. Nakano Y. Characterization of a vitamin B12 compound from unicellular eoccoluhophorid alga I Pletirocluysis carterae). JAgric Food Chem 2001:49:3486-9

Namour K Olivier J, Abdelmouttaleb 1, Adjalla C, Debard K. Salvat C. Gueant J. Transcobalamin codon 259 polymorphism in HT-29 and Caco-2 cells and in Caucasians: relation u> transcobalamin and homocysteine concentration in blood. Bioott 2001;97:1092-8 Nielsen R. Sorensen US. Bim H. Christensen El, Nexo E. Transcellular trans|>ort of vitamin B(!2) in LLC-PK.1 renal proximal tubule cells. ./ Am Sue Nephral 2001:12:1099 106

Percz-D'Gregorio RE. Miller RK. Transport and endogenous release of vitamin B12 in the dually perfused human placenta. JPediatr I998;I32:S35 S42 Pezacka L. Green R. Jacobsen DW. Glutathionylcobalamin as an intermediate in the formation of cobalamin coenzymes. Biochem Biophys Res Comm 1990:169:443 50 Puston JM. The relative carbon llux through the alpha- and the bcta-keto pathways of leucine metabolism../ Bio! Chew 1984:259:2059 61 Raa.x P. Schubert HI.. Warren MJ. Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum Celt Mal Life Sei 2000:57:1880-93 Riedel B, Fiskcrstrand T. Refsum H, Ueland PM Co-ordinate variations in methyl-malonyl-CoA mutase and methionine synthase, and the cobalamin cofactors in human glioma cells during nitrous oxide exposure and the subsequent recovery phase. Biochem J 1999;341:133-8 Russell-Jones GJ. Alpers DM. Vitamin B12 transporters. Phurmuceut Bioteclinol 1999:12:493-520

Sauer SW, Keim ML Hydroxocobalamin: improved public health readiness for cyanide disasters. Ann Etfierg Med 2001*37:635 -41 Seetharam B. Bose S. Li N. Cellular import of cobalamin (vitamin B-12). J Star 1999;129:1761-4

Toyoshima M. Grasbeck R. Cobalamin derivatives in subcellular fractions of porcine ileal enterocytes. Stand J Clin Luh Invest I987;47:277 84 Ward Nl:, Jones J. Maurice DV Essential role of adenosyleohalamin in leucine synthesis from beta-leucine in the domestic chicken. J Nurr 1988:118:159 64 Zlokovic BV Mattel CL, Matsubara F. McComb JG, Zheng G, McCluskey RT, Frangione B. Ghiso J. Glycoprotein 330 megabit: probable role in receptor-mediated transport of apolipoprotein .1 alone and in a complex \\ ith Alzheimer disease amyloid beta at the blood-brain and blood-ccrebrospinal fluid barriers. Pnac Mail Acad Sei USA 1996:93:4229 34

100 Pregnancy Tips

100 Pregnancy Tips

Prior to planning pregnancy, you should learn more about the things involved in getting pregnant. It involves carrying a baby inside you for nine months, caring for a child for a number of years, and many more. Consider these things, so that you can properly assess if you are ready for pregnancy. Get all these very important tips about pregnancy that you need to know.

Get My Free Ebook


Post a comment