Harpers

492 / CHAPTER 45H 3 CH 2 NCOCH 2 CH 2 NCH 3H 2 NCOCH R2 NCHH 33 C Co NH 3 C N CH 2 CH 2 CONH 2CHH 32 NCOCH 2 CH 3CH 2H 3 CCH 2C ONHCH 2 OCHH 3 COCH 2 CONH 2CH 2 CH 2 CONH 2HOCH 2O HOgastric mucosa. Gastric acid and pepsin release the vitaminfrom protein binding in food and make it availableto bind to cobalophilin, a binding protein secreted inthe saliva. In the duodenum, cobalophilin is hydrolyzed,releasing the vitamin for binding to intrinsicfactor. Pancreatic insufficiency can therefore be a factorin the development of vitamin B 12 deficiency, resultingin the excretion of cobalophilin-bound vitaminB 12 . Intrinsic factor binds the various vitamin B 12 vitamers,but not other corrinoids. Vitamin B 12 is absorbedfrom the distal third of the ileum via receptors thatbind the intrinsic factor-vitamin B 12 complex but notfree intrinsic factor or free vitamin.POONNCH 3CH 3Figure 45–13. Vitamin B 12 (cobalamin). R may bevaried to give the various forms of the vitamin, eg,R = CN – in cyanocobalamin; R = OH – in hydroxocobalamin;R = 5′-deoxyadenosyl in 5′-deoxyadenosylcobalamin;R = H 2 O in aquocobalamin; and R = CH 3 inmethylcobalamin.There Are Three VitaminB 12 -Dependent EnzymesMethylmalonyl CoA mutase, leucine aminomutase,and methionine synthase (Figure 45–14) are vitaminB 12 -dependent enzymes. Methylmalonyl CoA is formedas an intermediate in the catabolism of valine and bythe carboxylation of propionyl CoA arising in the catabolismof isoleucine, cholesterol, and, rarely, fattyacids with an odd number of carbon atoms—or directlyfrom propionate, a major product of microbial fermentationin ruminants. It undergoes vitamin B 12 -dependent rearrangement to succinyl-CoA, catalyzedby methylmalonyl-CoA isomerase (Figure 19–2). Theactivity of this enzyme is greatly reduced in vitamin B 12deficiency, leading to an accumulation of methylmalonyl-CoAand urinary excretion of methylmalonicacid, which provides a means of assessing vitamin B 12nutritional status.Vitamin B 12 Deficiency CausesPernicious AnemiaPernicious anemia arises when vitamin B 12 deficiencyblocks the metabolism of folic acid, leading to functionalfolate deficiency. This impairs erythropoiesis,causing immature precursors of erythrocytes to be releasedinto the circulation (megaloblastic anemia). Thecommonest cause of pernicious anemia is failure of theabsorption of vitamin B 12 rather than dietary deficiency.This can be due to failure of intrinsic factor secretioncaused by autoimmune disease of parietal cellsor to generation of anti-intrinsic factor antibodies.THERE ARE MULTIPLE FORMSOF FOLATE IN THE DIETThe active form of folic acid (pteroyl glutamate) istetrahydrofolate (Figure 45–15). The folates in foodsmay have up to seven additional glutamate residueslinked by γ-peptide bonds. In addition, all of the onecarbonsubstituted folates in Figure 45–15 may also bepresent in foods.The extent to which the different forms of folate canbe absorbed varies, and this must be allowed for in calculatingfolate intakes.SH(CH 2 ) 2H C NH +3COO –HomocysteineMethylMETHIONINESYNTHASEMethylcobalaminH B 124 folateH 3 CS(CH 2 ) 2H C NH + 3COO –MethionineH 4 folateFigure 45–14. Homocysteinuria and the folate trap.Vitamin B 12 deficiency leads to inhibition of methioninesynthase activity causing homocysteinuria and thetrapping of folate as methyltetrahydrofolate.