2r0m

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The effect of a Glu370Asp Mutation in Glutaryl-CoA Dehydrogenase on Proton Transfer to the Dienolate Intermediate

Structural highlights

2r0m is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.7Å
Ligands:4NI, FAD
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GCDH_HUMAN Defects in GCDH are the cause of glutaric aciduria type 1 (GA1) [MIM:231670. GA1 is an autosomal recessive metabolic disorder characterized by progressive dystonia and athetosis due to gliosis and neuronal loss in the basal ganglia.[1] [2] [3] [4] [5] [6]

Function

GCDH_HUMAN Catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. Isoform Short is inactive.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

We have determined steady-state rate constants and net rate constants for the chemical steps in the catalytic pathway catalyzed by the E370D mutant of glutaryl-CoA dehydrogenase and compared them with those of the wild-type dehydrogenase. We sought rationales for changes in these rate constants in the structure of the mutant cocrystallized with the alternate substrate, 4-nitrobutyric acid. Substitution of aspartate for E370, the catalytic base, results in a 24% decrease in the rate constant for proton abstraction at C-2 of 3-thiaglutaryl-CoA as the distance between C-2 of the ligand and the closest carboxyl oxygen at residue 370 increases from 2.9 A to 3.1 A. The net rate constant for flavin reduction due to hydride transfer from C-3 of the natural substrate, which includes proton abstraction at C-2, to N5 of the flavin decreases by 81% due to the mutation, although the distance increases only by 0.7 A. The intensities of charge-transfer bands associated with the enolate of 3-thiaglutaryl-CoA, the reductive half-reaction (reduced flavin with oxidized form of substrate), and the dienolate following decarboxylation are considerably diminished. Structural investigation suggests that the increased distance and the change in angle of the S-C1(=O)-C2 plane of the substrate with the isoalloxazine substantially alter rates of the reductive and oxidative half-reactions. This change in active site geometry also changes the position of protonation of the four carbon dienolate intermediate to produce kinetically favorable product, vinylacetyl-CoA, which is further isomerized to the thermodynamically stable normal product, crotonyl-CoA.

The effect of a Glu370Asp mutation in glutaryl-CoA dehydrogenase on proton transfer to the dienolate intermediate.,Rao KS, Fu Z, Albro M, Narayanan B, Baddam S, Lee HJ, Kim JJ, Frerman FE Biochemistry. 2007 Dec 18;46(50):14468-77. Epub 2007 Nov 17. PMID:18020372[7]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
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Decarboxylating and nondecarboxylating glutaryl-coenzyme A dehydrogenases in the aromatic metabolism of obligately anaerobic bacteria.
Wischgoll et al. (2009)
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4 other articles
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See Also

References

  1. ↑ Keyser B, Muhlhausen C, Dickmanns A, Christensen E, Muschol N, Ullrich K, Braulke T. Disease-causing missense mutations affect enzymatic activity, stability and oligomerization of glutaryl-CoA dehydrogenase (GCDH). Hum Mol Genet. 2008 Dec 15;17(24):3854-63. doi: 10.1093/hmg/ddn284. Epub 2008 Sep, 5. PMID:18775954 doi:10.1093/hmg/ddn284
  2. ↑ Goodman SI, Kratz LE, DiGiulio KA, Biery BJ, Goodman KE, Isaya G, Frerman FE. Cloning of glutaryl-CoA dehydrogenase cDNA, and expression of wild type and mutant enzymes in Escherichia coli. Hum Mol Genet. 1995 Sep;4(9):1493-8. PMID:8541831
  3. ↑ Schwartz M, Christensen E, Superti-Furga A, Brandt NJ. The human glutaryl-CoA dehydrogenase gene: report of intronic sequences and of 13 novel mutations causing glutaric aciduria type I. Hum Genet. 1998 Apr;102(4):452-8. PMID:9600243
  4. ↑ Biery BJ, Stein DE, Morton DH, Goodman SI. Gene structure and mutations of glutaryl-coenzyme A dehydrogenase: impaired association of enzyme subunits that is due to an A421V substitution causes glutaric acidemia type I in the Amish. Am J Hum Genet. 1996 Nov;59(5):1006-11. PMID:8900227
  5. ↑ Anikster Y, Shaag A, Joseph A, Mandel H, Ben-Zeev B, Christensen E, Elpeleg ON. Glutaric aciduria type I in the Arab and Jewish communities in Israel. Am J Hum Genet. 1996 Nov;59(5):1012-8. PMID:8900228
  6. ↑ Muhlhausen C, Christensen E, Schwartz M, Muschol N, Ullrich K, Lukacs Z. Severe phenotype despite high residual glutaryl-CoA dehydrogenase activity: a novel mutation in a Turkish patient with glutaric aciduria type I. J Inherit Metab Dis. 2003;26(7):713-4. PMID:14707522
  7. ↑ Rao KS, Fu Z, Albro M, Narayanan B, Baddam S, Lee HJ, Kim JJ, Frerman FE. The effect of a Glu370Asp mutation in glutaryl-CoA dehydrogenase on proton transfer to the dienolate intermediate. Biochemistry. 2007 Dec 18;46(50):14468-77. Epub 2007 Nov 17. PMID:18020372 doi:10.1021/bi7009597

Contents


PDB ID 2r0m

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