| Structural highlights
6d5x is a 3 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , |
| Gene: | MMAB (HUMAN) |
| Activity: | Cob(I)yrinic acid a,c-diamide adenosyltransferase, with EC number 2.5.1.17 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
[MMAB_HUMAN] Defects in MMAB are the cause of methylmalonic aciduria type cblB (MMAB) [MIM:251110]; also known as methylmalonic aciduria type B or vitamin B12-responsive methylmalonicaciduria of cblB complementation type. MMAB is a disorder of methylmalonate and cobalamin metabolism due to defective synthesis of adenosylcobalamin. Inheritance is autosomal recessive.[1] [2] [3]
Publication Abstract from PubMed
A sophisticated intracellular trafficking pathway in humans is used to tailor vitamin B12 into its active cofactor forms, and to deliver it to two known B12-dependent enzymes. Herein, we report an unexpected strategy for cellular retention of B12, an essential and reactive cofactor. If methylmalonyl-CoA mutase is unavailable to accept the coenzyme B12 product of adenosyltransferase, the latter catalyzes homolytic scission of the cobalt-carbon bond in an unconventional reversal of the nucleophilic displacement reaction that was used to make it. The resulting homolysis product binds more tightly to adenosyltransferase than does coenzyme B12, facilitating cofactor retention. We have trapped, and characterized spectroscopically, an intermediate in which the cobalt-carbon bond is weakened prior to being broken. The physiological relevance of this sacrificial catalytic activity for cofactor retention is supported by the significantly lower coenzyme B12 concentration in patients with dysfunctional methylmalonyl-CoA mutase but normal adenosyltransferase activity.
Sacrificial Cobalt-Carbon Bond Homolysis in Coenzyme B12 as a Cofactor Conservation Strategy.,Campanello GC, Ruetz M, Dodge GJ, Gouda H, Gupta A, Twahir UT, Killian MM, Watkins D, Rosenblatt DS, Brunold TC, Warncke K, Smith JL, Banerjee R J Am Chem Soc. 2018 Oct 8. doi: 10.1021/jacs.8b08659. PMID:30282455[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Dobson CM, Wai T, Leclerc D, Kadir H, Narang M, Lerner-Ellis JP, Hudson TJ, Rosenblatt DS, Gravel RA. Identification of the gene responsible for the cblB complementation group of vitamin B12-dependent methylmalonic aciduria. Hum Mol Genet. 2002 Dec 15;11(26):3361-9. PMID:12471062
- ↑ Leal NA, Park SD, Kima PE, Bobik TA. Identification of the human and bovine ATP:Cob(I)alamin adenosyltransferase cDNAs based on complementation of a bacterial mutant. J Biol Chem. 2003 Mar 14;278(11):9227-34. Epub 2003 Jan 3. PMID:12514191 doi:10.1074/jbc.M212739200
- ↑ Martinez MA, Rincon A, Desviat LR, Merinero B, Ugarte M, Perez B. Genetic analysis of three genes causing isolated methylmalonic acidemia: identification of 21 novel allelic variants. Mol Genet Metab. 2005 Apr;84(4):317-25. Epub 2005 Jan 22. PMID:15781192 doi:S1096-7192(04)00307-5
- ↑ Campanello GC, Ruetz M, Dodge GJ, Gouda H, Gupta A, Twahir UT, Killian MM, Watkins D, Rosenblatt DS, Brunold TC, Warncke K, Smith JL, Banerjee R. Sacrificial Cobalt-Carbon Bond Homolysis in Coenzyme B12 as a Cofactor Conservation Strategy. J Am Chem Soc. 2018 Oct 8. doi: 10.1021/jacs.8b08659. PMID:30282455 doi:http://dx.doi.org/10.1021/jacs.8b08659
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