Inherited disorders of cobalamin metabolism

Qureshi, A; Rosenblatt, David S.; Cooper, Bernard A.

doi:10.1016/1040-8428(94)90022-1

Cited by 40 publications

(23 citation statements)

References 107 publications

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“…Although TC binds only ϳ25% of the circulating vitamin, it is responsible for the delivery of B 12 to most tissues. Indeed, whereas inherited TC deficiency is associated with severe megaloblastic anemia, patients with HC deficiency may be asymptomatic with normal levels of MMA despite low total serum B 12 (110). This is also reflected in the half-life of the two carrier proteins, being Ͻ2 h for TC compared with several days for HC.…”

Section: Vitamin B12mentioning

confidence: 92%

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The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

Birn

2006

American Journal of Physiology-Renal Physiology

125

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Over the past 10 years, animal studies have uncovered the molecular mechanisms for the renal tubular recovery of filtered vitamin and vitamin carrier proteins. Relatively few endocytic receptors are responsible for the proximal tubule uptake of a number of different vitamins, preventing urinary losses. In addition to vitamin conservation, tubular uptake by endocytosis is important to vitamin metabolism and homeostasis. The present review focuses on the receptors involved in renal tubular recovery of folate, vitamin B12, and their carrier proteins. The multiligand receptor megalin is important for the uptake and tubular accumulation of vitamin B12. During vitamin load, the kidney accumulates large amounts of free vitamin B12, suggesting a possible storage function. In addition, vitamin B12 is metabolized in the kidney, suggesting a role in vitamin homeostasis. The folate receptor is important for the conservation of folate, mediating endocytosis of the vitamin. Interaction between the structurally closely related, soluble folate-binding protein and megalin suggests that megalin plays an additional role in the uptake of folate bound to filtered folate-binding protein. A third endocytic receptor, the intrinsic factor-B12 receptor cubilin-amnionless complex, is essential to the renal tubular uptake of albumin, a carrier of folate. In conclusion, uptake is mediated by interaction with specific endocytic receptors also involved in the renal uptake of other vitamins and vitamin carriers. Little is known about the mechanisms regulating intracellular transport and release of vitamins, and whereas tubular uptake is a constitutive process, this may be regulated, e.g., by vitamin status.

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Section: Vitamin B12mentioning

confidence: 92%

“…The processes are reviewed in Refs. 25,110,and 123. DHF,dihydrofolate. folate bound to high-affinity serum proteins varies between species, being high in pigs (83) and relatively low in rodents such as mice and rats (127).…”

Section: Folatementioning

confidence: 99%

The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

Birn

2006

American Journal of Physiology-Renal Physiology

125

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“…However, despite the versatility of the coenzyme in metabolism, the actual number of known B 12 -dependent enzymes remains comparatively small and, therefore, most organisms require cobalamin in vanishingly small quantities. Humans require between 1-2 mg per day, which is ingested from our diet and is taken up by an elaborate absorption mechanism [5]. As will be highlighted later, cobalamin is made only by members of the Archea and certain eubacteria and it is to this biosynthesis that we will shortly turn our attention since it represents one of the most complex biosynthetic pathways known in Nature.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum

Raux

Schubert

Warren

2000

CMLS, Cell. Mol. Life Sci.

187

153

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The biosynthesis of cobalamin (vitamin B12) is described, revealing how the concerted action of around 30 enzyme-mediated steps results in the synthesis of one of Nature's most structurally complex 'small molecules'. The plethora of genome sequences has meant that bacteria capable of cobalamin synthesis can be easily identified and their biosynthetic genes compared. Whereas only a few years ago cobalamin synthesis was thought to occur by one of two routes, there are apparently a number of variations on these two pathways, where the major differences seem to be concerned with the process of ring contraction. A comparison of what is currently known about these pathways is presented. Finally, the process of cobalt chelation is discussed and the structure/function of the cobalt chelatase associated with the oxygen-independent pathway (CbiK) is described.

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“…However, mammalian cells are devoid of the enzymatic capacity for folate biosynthesis and thus are absolutely dependent on folate uptake from exogenous dietary sources (7). Therefore, folate deficiency may impair the de novo biosynthesis of purines and thymidylate and thereby disrupt DNA and RNA metabolism, homocysteine remethylation, methionine biosynthesis, and subsequent formation of S-adenosylmethionine, the universal methyl donor, which in turn may lead to the impairment of methylation reactions (1)(2)(3)(4)(5)(6). Based on their key role in cellular metabolism, folate cofactors are efficiently retained in cells via polyglutamylation, an ATPdependent reaction in which up to 9 eq of glutamate units are added to the ␥-carboxyl residue of folate cofactors (8,9) (see Fig.…”

mentioning

confidence: 99%

“…Reduced folate cofactors play an essential role as one-carbon donors and acceptors in several crucial intracellular metabolic reactions (1)(2)(3)(4)(5)(6). However, mammalian cells are devoid of the enzymatic capacity for folate biosynthesis and thus are absolutely dependent on folate uptake from exogenous dietary sources (7).…”

mentioning

confidence: 99%

The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

Ifergan

Jansen

Assaraf

2008

Journal of Biological Chemistry

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The reduced folate carrier (RFC), a bidirectional anion transporter, is the major uptake route of reduced folates essential for a spectrum of biochemical reactions and thus cellular proliferation. However, here we show that ectopic overexpression of the RFC, but not of folate receptor ␣, a high affinity unidirectional folate uptake route serving here as a negative control, resulted in an ϳ15-fold decline in cellular viability in medium lacking folates but not in folate-containing medium. Moreover to explore possible mechanisms of adaptation to folate deficiency in various cell lines that express the endogenous RFC, we first determined the gene expression status of the following genes: (a) RFC, (b) ATP-driven folate exporters (i.e. MRP1, MRP5, and breast cancer resistance protein), and (c) folylpoly-␥-glutamate synthetase and ␥-glutamate hydrolase (GGH), enzymes catalyzing folate polyglutamylation and hydrolysis, respectively. Upon 3-7 days of folate deprivation, semiquantitative reverse transcription-PCR analysis revealed a specific ϳ2.5-fold decrease in RFC mRNA levels in both breast cancer and T-cell leukemia cell lines that was accompanied by a consistent fall in methotrexate influx, serving here as an RFC transport activity assay. Likewise a 2.4-fold decrease in GGH mRNA levels and ϳ19% decreased GGH activity was documented for folate-deprived breast cancer cells. These results along with those of a novel mathematical biomodeling devised here suggest that upon severe short term (i.e. up to 7 days) folate deprivation RFC transport activity becomes detrimental as RFC, but not ATPdriven folate exporters, efficiently extrudes folate monoglutamates out of cells. Hence down-regulation of RFC and GGH may serve as a novel adaptive response to severe folate deficiency.

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Inherited disorders of cobalamin metabolism

Cited by 40 publications

References 107 publications

The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum

The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

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Inherited disorders of cobalamin metabolism

Cited by 40 publications

References 107 publications

The kidney in vitamin B12and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

The kidney in vitamin B12and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

Biosynthesis of cobalamin (vitamin B12): a bacterial conundrum

The Reduced Folate Carrier (RFC) Is Cytotoxic to Cells under Conditions of Severe Folate Deprivation

Contact Info

Product

Resources

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The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins

The kidney in vitamin B₁₂and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins