Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor

Allen, Robert H.; Seetharam, Bellur; Allen, Nancy C.; Podell, Elaine R.; Alpers, David H.

doi:10.1172/jci109083

Cited by 77 publications

(28 citation statements)

References 12 publications

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“…Cbl-analogues were not revealed in cow milk and the amount of TC-Cbl (3 nmol per liter) was quite sufficient to satisfy the demands of daily intake for man (1 nmol) [35]. The instability of TC-Cbl at pH 2 guaranties the liberation of Cbl in acidic medium of human stomach and its binding to human IF and HC [37,38]. It means that cow milk is an appropriate source of B~2 for man.…”

Section: Discussionmentioning

confidence: 99%

Transcobalamin from cow milk: isolation and physico-chemical properties

Fedosov

Petersen

Nexø

1996

Biochimica et Biophysica Acta (BBA) - Protein Structure and Mol

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The concentration of endogenous cobalamin (Cbl) in cow milk was 3.3 nM while the Cbl-binding capacity was 0.05 nM. Both endogenous and newly added Cbl showed similar quantitative distribution between a 280 kDa protein complex (45%) and a 43 kDa Cbl-binder (55%). Long time incubation, as well as urea treatment, was accompanied by a slow release of the 43 kDa Cbl-binder from the 280 kDa fraction. No other Cbl-binding proteins appeared after these procedures. The 43 kDa binder from cow milk, depleted of the ligand by urea treatment, ieacted with Cbl even in the presence of a B12-analogue cobinamide (Cbi) at the ratio Cbl:Cbi = 1:40. The Stokes radius of the binder changed from 2.7 nm for the Cbl-free protein to 2.5 nm for the Cbl-saturated form and the Cbl-saturated binder was able to displace human transcobalamin (TC) from the TC-receptor. The interaction between the protein and Cbl was significantly suppressed at pH 2.0. The N-terminal sequence of the purified 43 kDa Cbl-binder revealed homology with TC from human and rabbit plasma. In conclusion we have shown that TC is the main Cbl-binding protein in cow milk. This is surprising, since previous studies on human and rat milk have shown another Cbl-binder, apo-haptocorrin, to be the dominating Cbl-binding protein.

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Section: Discussionmentioning

confidence: 99%

Transcobalamin from cow milk: isolation and physico-chemical properties

Fedosov

Petersen

Nexø

1996

Biochimica et Biophysica Acta (BBA) - Protein Structure and Mol

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“…7,8 Haptocorrin itself is degraded in the duodenum by proteases stemming from the pancreas, following which intrinsic factor (IF) sequesters the released Cbl. 7,8 IF is synthesized and secreted by parietal cells of the stomach, and its deficiency, either due to inborn errors or an autoimmunity against the parietal cells, results in classical pernicious anemia. 9,10 At the terminal ileum, IFbound Cbl (IF-Cbl) is recognized by distinct cells (polarized epithelial enterocytes), which express a complex receptor composed of a heterodimer of amnionless and cubilin (cubam) in the apical brush border, which mediates cellular absorption of Cbl via endocytosis.…”

Section: Cobalamin Metabolism-structure and Intakementioning

confidence: 99%

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Froese

Fowler

Baumgartner

2019

J of Inher Metab Disea

292

187

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Vitamin B12 (cobalamin, Cbl) is a nutrient essential to human health. Due to its complex structure and dual cofactor forms, Cbl undergoes a complicated series of absorptive and processing steps before serving as cofactor for the enzymes methylmalonyl‐CoA mutase and methionine synthase. Methylmalonyl‐CoA mutase is required for the catabolism of certain (branched‐chain) amino acids into an anaplerotic substrate in the mitochondrion, and dysfunction of the enzyme itself or in production of its cofactor adenosyl‐Cbl result in an inability to successfully undergo protein catabolism with concomitant mitochondrial energy disruption. Methionine synthase catalyzes the methyl‐Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S‐adenosylmethionine, the most important cellular methyl‐donor. Disruption of methionine synthase has wide‐ranging implications for all methylation‐dependent reactions, including epigenetic modification, but also for the intracellular folate pathway, since methionine synthase uses 5‐methyltetrahydrofolate as a one‐carbon donor. Folate‐bound one‐carbon units are also required for deoxythymidine monophosphate and de novo purine synthesis; therefore, the flow of single carbon units to each of these pathways must be regulated based on cellular needs. This review provides an overview on Cbl metabolism with a brief description of absorption and intracellular metabolic pathways. It also provides a description of folate‐mediated one‐carbon metabolism and its intersection with Cbl at the methionine cycle. Finally, a summary of recent advances in understanding of how both pathways are regulated is presented.

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“…These authors showed that macromolecular complexes--such as the so-called R-binders in the saliva which compete with the intrinsic factor for vitamin B12 binding--are broken down by trypsin making normal vitamin B~2 absorption possible. This theory has been given support recently by the studies performed by Allen et al on adults with EPI [1]. They were able to show that the cobalamin analogue "cobinamide" which is bound almost exclusively to the R-binders and hardly at all to the intrinsic factor, corrected the malabsorption of vitamin B12 in patients with EPI.…”

Section: Discussionmentioning

confidence: 78%

Vitamin B12 absorption and exocrine pancreatic insufficiency in childhood

et al. 1981

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The absorption of vitamin B12, labelled with radioactive 58Co, was measured in 19 patients with cystic fibrosis and one child with the Shwachman-Diamond syndrome using the whole body counting technique. We found vitamin B12 absorption reduced to 7.97 on average, compared to 59.2% for the control group. The low vitamin B12 absorption correlated well with the reduced fat retention coefficients. After adding 0.212 pancreatin to the radioactive vitamin B12 test dose, the absorption quotas improved in all cases, the average being 61%. A meal poor in vitamin B12 tended to increase the absorption of the radioactive test dose to 23% on average. As yet there is no satisfactory explanation for the effect of the diet on the absorption of vitamin B12 in exocrine pancreatic insufficiency. This could be the reason why the malabsorption of vitamin B12 in patients with EPI can go unnoticed for many years and could possibly explain why vitamin B12 malabsorption in exocrine pancreatic insufficiency does not cause symptoms and signs of vitamin B12 deficiency for many years.

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Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor

Abstract: A B S T R A C T In vitro studies indicate that [57Co]cobalamin (Cbl) is preferentially bound to salivary R protein as opposed to intrinsic factor (IF)

Cited by 77 publications

References 12 publications

Transcobalamin from cow milk: isolation and physico-chemical properties

Transcobalamin from cow milk: isolation and physico-chemical properties

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Vitamin B12 absorption and exocrine pancreatic insufficiency in childhood

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Correction of Cobalamin Malabsorption in Pancreatic Insufficiency with a Cobalamin Analogue that Binds with High Affinity to R Protein but not to Intrinsic Factor

Abstract: A B S T R A C T In vitro studies indicate that [57Co]cobalamin (Cbl) is preferentially bound to salivary R protein as opposed to intrinsic factor (IF)

Cited by 77 publications

References 12 publications

Transcobalamin from cow milk: isolation and physico-chemical properties

Transcobalamin from cow milk: isolation and physico-chemical properties

Vitamin B12, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation

Vitamin B12 absorption and exocrine pancreatic insufficiency in childhood

Contact Info

Product

Resources

About

Vitamin B₁₂, folate, and the methionine remethylation cycle—biochemistry, pathways, and regulation