Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza).

Haurani, Farid I.; Hall, Charles A.; Rubin, R. A.

doi:10.1172/jci109580

Cited by 56 publications

(11 citation statements)

References 30 publications

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“…However, it can be impaired by mutations inside the ligand-binding site of a Cbl transporter or at the receptor-transporter interface. Regarding TC in this respect, some clinical cases of disorders have indeed been linked to defective protein in the patient (10,11). Yet the main variant forms of this transporter stem from common polymorphisms of the TC gene (12).…”

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confidence: 99%

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Wuerges

Garau²,

Geremia³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

166

216

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Cobalamin (Cbl, vitamin B12) serves for two essential cofactors in mammals. The pathway for its intestinal absorption, plasma transport, and cellular uptake uses cell surface receptors and three Cbl-transporting proteins, haptocorrin, intrinsic factor, and transcobalamin (TC). We present the structure determination of a member of the mammalian Cbl-transporter family. The crystal structures of recombinant human and bovine holo-TCs reveal a two-domain architecture, with an N-terminal ␣6-␣6 barrel and a smaller C-terminal domain. One Cbl molecule in base-on conformation is buried inside the domain interface. Structural data combined with previous binding assays indicate a domain motion in the first step of Cbl binding. In a second step, the weakly coordinated ligand H 2O at the upper axial side of added H2O-Cbl is displaced by a histidine residue of the ␣6-␣6 barrel. Analysis of amino acid conservation on TC's surface in orthologous proteins suggests the location of the TC-receptor-recognition site in an extended region on the ␣6-␣6 barrel. The TC structure allows for the mapping of sites of amino acid variation due to polymorphisms of the human TC gene. Structural information is used to predict the overall fold of haptocorrin and intrinsic factor and permits a rational approach to the design of new Cbl-based bioconjugates for diagnostic or therapeutic drug delivery.cobalamin ͉ crystal structure ͉ P259R polymorphism ͉ transport protein

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confidence: 99%

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Wuerges

Garau²,

Geremia³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

166

216

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“…available to these earlier investigators and the contribution of Cbl binders leaking from blood cells in vitro had not been fully reported and was, therefore, not controlled. Recently C b l binding by serum could be studied more fully in one case (Hall et al, 1979). There was no unsaturated binding capacity for Cbl.…”

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confidence: 99%

Atypical cobalamin binding in the serum of congenital deficiency of transcobalamin II

Hall

Begley

1982

Br J Haematol

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The serum cobalamin (Cb 1) binding patterns were described in nine children with congenital deficiency of transcobalamin II (TC II). Immunoreactive TC II was less than 100 pg/ml TC II-Cb 1 equivalent in eight and 150 pg/ml in the ninth. There was neither endogenous TC II-Cb 1 (holo TC II) nor apo TC II. Thus, the defect was characterized by the absence of any binding of Cb 1 to TC II either in vivo or in vitro and either non-detectable or much reduced immunoreactive TC II. Only the serum from an untreated infant bound any added Cb 1 at all, but in every sera there was binding of endogenous Cb 1 to a substance of the molecular size of albumin. Native Cb 1 was also bound to R binder and in some instances was incorporated into large complexes. The precise nature, cause and consequences of this atypical binding are unknown.

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“…Abnormally high circulating levels of unsaturated (apo) TCII without apparent disturbance of Cbl metabolism have been reported in various conditions (Kane et al, 1976;Carmel and Hollander, 1978), but endogenous (holo) TCII levels were not measured• In our case the plasma holo-TCII level was more than five times the upper normal limit while apo-TClI was low. Since this patient's lymphocytes synthesized less Ado-Cbl when cultured with his own plasma than when cultured with compatible control plasma, it is possible that his holo-TCII may have been ineffective and that the measurable Cbl attached was more tightly bound than normal, as in Haurani's case (Haurani et al, 1979).…”

Section: Discussionmentioning

confidence: 94%

Abnormal cobalamin metabolism in a case of juvenile pernicious anaemia with neurological symptoms

Linnell

Quadros

England

et al. 1981

J of Inher Metab Disea

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Studies of cobalamin metabolism in a case of juvenile pernicious anaemia during haematological remission showed that while plasma cobalamins were normal there was some depletion of erythrocyte cobalamins. In addition, the plasma distribution of apo-and holo-transcobalamins was markedly abnormal, holo-TCII being increased, yet the patient's plasma promoted less cellular synthesis of adenosylcobalamin by cultured lymphocytes than did plasma from a control subject. The results suggest that hoto-TCII may in this case have been ineffective and provide further evidence for the importance of TCII in intracellular synthesis of adenosylcobalamin.Cobalamin deficiency in pernicious anaemia (PA) results from genetically absent or ineffective gastric intrinsic factor with impaired intestinal absorption and loss of biliary cobalamins. Regular parenteral administration ofhydroxocobalamin (OH-Cbl) normally restores cellular and tissue levels of the two coenzymes adenosylcobalamin (Ado-Cbl) and methylcobalamin (Me-Cbl), maintaining the patient in haematological remission.We have investigated cobalamin metabolism in a case of juvenile PA diagnosed by Schilling test, who, despite continued therapy with parenteral OH-Cbl and oral folate, developed neurological symptoms with ataxia, parasthesiae, impaired dexterity and some visual loss. METHODSCobalamins in plasma and erythrocytes were estimated , by chromatography and bioautography (Linnell et al., 1974). Transcobalamins TC0, TCI and TCII were separated on Sephadex G.200 and the total Cbl attached to each TC was estimated by radioisotopic assay (England et al., 1976). Uptake and conversion of [57Co]CN-Cbl in phytohaemagglutinin (PHA)-stimulated lymphocytes in vitro was measured as previously described (Quadros et al., 1976). RESULTS Estimation of plasma cobalamins 4 weeks after OH-Cbl(1 mg i.m.) showed no marked abnormality, but in erythrocytes OH-Cbl was low and the level of Ado-Cbl was close to the lower limit ()f normal (Table 1). Similarly low levels of OH-Cbl and Ado-Cbl were detected in erythrocyte samples 4 and 6 months later, despite continuing OH-Cbl therapy and daily oral folate.Plasma Cbt binding capacity (UBBC) was normal (920 pg/ml), but binding of [57Co]CN-Cbl to each transcobalamin showed a markedly disturbed distribution, more being attached to TCI and less to TCII than normal (Figure 1). Analysis of the endogenous Cbl distribution showed that the total Cbl carried by TCII (334 pg/ml) was more than four times the upper limit of normal (normal range 7-82pg/ml) and, in addition, about 10% was.bound to a protein of the molecular weight of albumin.

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Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza).

Abstract: A B S T R A C T A 34-year-old Black wom-an had severe megaloblastic anemia in childhood. Initially, and over the years, she responded well to miassive doses of parenteral cobalamin (Cbl)

Cited by 56 publications

References 30 publications

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Atypical cobalamin binding in the serum of congenital deficiency of transcobalamin II

Abnormal cobalamin metabolism in a case of juvenile pernicious anaemia with neurological symptoms

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Megaloblastic anemia as a result of an abnormal transcobalamin II (Cardeza).

Abstract: A B S T R A C T A 34-year-old Black wom-an had severe megaloblastic anemia in childhood. Initially, and over the years, she responded well to miassive doses of parenteral cobalamin (Cbl)

Cited by 56 publications

References 30 publications

Structural basis for mammalian vitamin B 12 transport by transcobalamin

Structural basis for mammalian vitamin B 12 transport by transcobalamin

Atypical cobalamin binding in the serum of congenital deficiency of transcobalamin II

Abnormal cobalamin metabolism in a case of juvenile pernicious anaemia with neurological symptoms

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Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin

Structural basis for mammalian vitamin B ₁₂ transport by transcobalamin