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Vitamin B12 transport proteins: crystallographic analysis of beta-axial ligand substitutions in cobalamin bound to transcobalamin.

Wuerges J, Geremia S, Fedosov SN, Randaccio L
IUBMB Life 59 722-9 (2007)
Cited: 17 times
EuropePMC logo PMID: 17943552

Abstract

Cobalamin (Cbl, vitamin B12) is an essential micronutrient that is synthesized only by bacteria. Mammals have developed a complex system for internalization of this vitamin from the diet. Three binding proteins (haptocorrin, intrinsic factor, transcobalamin (TC)) and several specific cell surface receptors are involved in the process of intestinal absorption, plasma transport and cellular uptake. The recent literature on the binding proteins is briefly reviewed. A structural study is presented addressing a unique feature of TC among the three proteins, i.e., the displacement of the weak Co(III)-ligand H2O at the upper (or beta) axial side of H2O-Cbl by a histidine side chain. We have investigated crystallographically the beta-ligand exchange on Cbl bound to TC by crystallization of bovine holo-TC in the presence of either cyanide or sulfite. The resulting electron density maps show that the histidine side chain has been displaced by an exogenous ligand CN(-) or SO(3)(-2)to a lower extent than expected based on their higher affinity for Co and excess concentration with respect to histidine. This may reflect either reduced affinities of CN(-) and SO(3)(-2)or the advantageous binding of the protein-integrated His-residue when competing for the beta-site of Cbl bound to TC. The loop hosting the histidine residue appears more flexible after disruption of the coordination bond His-Cbl but no other differences are observed in the overall structure of holo-TC. These structural results are discussed in relation to a possible physiological role of histidine substitution for H2O and regarding the role of beta-conjugated Cbl-analogues recently proposed for targeted delivery of imaging agents.

Reviews citing this publication (6)

  1. Advances in the understanding of cobalamin assimilation and metabolism. Quadros EV. Br J Haematol 148 195-204 (2010)
  2. Vitamin B12: unique metalorganic compounds and the most complex vitamins. Randaccio L, Geremia S, Demitri N, Wuerges J. Molecules 15 3228-3259 (2010)
  3. Vitamin B12 in drug delivery: breaking through the barriers to a B12 bioconjugate pharmaceutical. Clardy SM, Allis DG, Fairchild TJ, Doyle RP. Expert Opin Drug Deliv 8 127-140 (2011)
  4. An update on vitamin B12-related gene polymorphisms and B12 status. Surendran S, Adaikalakoteswari A, Saravanan P, Shatwaan IA, Lovegrove JA, Vimaleswaran KS. Genes Nutr 13 2 (2018)
  5. Anemia in nephrotic syndrome: approach to evaluation and treatment. Iorember F, Aviles D. Pediatr Nephrol 32 1323-1330 (2017)
  6. Vitamin B12 in Foods, Food Supplements, and Medicines-A Review of Its Role and Properties with a Focus on Its Stability. Temova Rakuša Ž, Roškar R, Hickey N, Geremia S. Molecules 28 240 (2022)

Articles citing this publication (11)

  1. Application of the PM6 method to modeling proteins. Stewart JJ. J Mol Model 15 765-805 (2009)
  2. Functional and structural characterization of an ECF-type ABC transporter for vitamin B12. Santos JA, Rempel S, Mous ST, Pereira CT, Ter Beek J, de Gier JW, Guskov A, Slotboom DJ. Elife 7 e35828 (2018)
  3. Redox-Linked Coordination Chemistry Directs Vitamin B12 Trafficking. Banerjee R, Gouda H, Pillay S. Acc Chem Res 54 2003-2013 (2021)
  4. Cysteine-mediated decyanation of vitamin B12 by the predicted membrane transporter BtuM. Rempel S, Colucci E, de Gier JW, Guskov A, Slotboom DJ. Nat Commun 9 3038 (2018)
  5. Release of toxic Gd3+ ions to tumour cells by vitamin B12 bioconjugates. Siega P, Wuerges J, Arena F, Gianolio E, Fedosov SN, Dreos R, Geremia S, Aime S, Randaccio L. Chemistry 15 7980-7989 (2009)
  6. The extracellular heme-binding protein HbpS from the soil bacterium Streptomyces reticuli is an aquo-cobalamin binder. Ortiz de Orué Lucana D, Fedosov SN, Wedderhoff I, Che EN, Torda AE. J Biol Chem 289 34214-34228 (2014)
  7. Polymorphisms in transcobalamin II gene is associated with coronary artery disease in Indian population. Garg G, Kumar J, Tanwar VS, Basak T, Seth S, Karthikeyan G, Sengupta S. Biomarkers 17 119-124 (2012)
  8. Vitamin B12 Phosphate Conjugation and Its Effect on Binding to the Human B12 -Binding Proteins Intrinsic Factor and Haptocorrin. Ó Proinsias K, Ociepa M, Pluta K, Chromiński M, Nexo E, Gryko D. Chemistry 22 8282-8289 (2016)
  9. 5'-Vitamin B12 derivatives suitable for bioconjugation via the amide bond. Jackowska A, Chromiński M, Giedyk M, Gryko D. Org Biomol Chem 16 936-943 (2018)
  10. A novel TCN2 mutation with unusual clinical manifestations of hemolytic crisis and unexplained metabolic acidosis: expanding the genotype and phenotype of transcobalamin II deficiency. Pongphitcha P, Sirachainan N, Khongkraparn A, Tim-Aroon T, Songdej D, Wattanasirichaigoon D. BMC Pediatr 22 233 (2022)
  11. Organometallic DNA-B12 Conjugates as Potential Oligonucleotide Vectors: Synthesis and Structural and Binding Studies with Human Cobalamin-Transport Proteins. Mutti E, Hunger M, Fedosov S, Nexo E, Kräutler B. Chembiochem 18 2280-2291 (2017)


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