| Structural highlights
1egc is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | ,
| | Activity: | Oxidoreductase, with EC number 1.3.8.8 and 1.3.8.9 1.3.8.7, 1.3.8.8 and 1.3.8.9 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[ACADM_HUMAN] Defects in ACADM are the cause of acyl-CoA dehydrogenase medium-chain deficiency (ACADMD) [MIM:201450]. It is an autosomal recessive disease which causes fasting hypoglycemia, hepatic dysfunction, and encephalopathy, often resulting in death in infancy.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15]
Function
[ACADM_HUMAN] This enzyme is specific for acyl chain lengths of 4 to 16.
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
Crystal structures of the wild type human medium-chain acyl-CoA dehydrogenase (MCADH) and a double mutant in which its active center base-arrangement has been altered to that of long chain acyl-CoA dehydrogenase (LCADH), Glu376Gly/Thr255Glu, have been determined by X-ray crystallography at 2.75 and 2.4 A resolution, respectively. The catalytic base responsible for the alpha-proton abstraction from the thioester substrate is Glu376 in MCADH, while that in LCADH is Glu255 (MCADH numbering), located over 100 residues away in its primary amino acid sequence. The structures of the mutant complexed with C8-, C12, and C14-CoA have also been determined. The human enzyme structure is essentially the same as that of the pig enzyme. The structure of the mutant is unchanged upon ligand binding except for the conformations of a few side chains in the active site cavity. The substrate with chain length longer than C12 binds to the enzyme in multiple conformations at its omega-end. Glu255 has two conformations, "active" and "resting" forms, with the latter apparently stabilized by forming a hydrogen bond with Glu99. Both the direction in which Glu255 approaches the C alpha atom of the substrate and the distance between the Glu255 carboxylate and the C alpha atom are different from those of Glu376; these factors are responsible for the intrinsic differences in the kinetic properties as well as the substrate specificity. Solvent accessible space at the "midsection" of the active site cavity, where the C alpha-C beta bond of the thioester substrate and the isoalloxazine ring of the FAD are located, is larger in the mutant than in the wild type enzyme, implying greater O2 accessibility in the mutant which might account for the higher oxygen reactivity.
Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity.,Lee HJ, Wang M, Paschke R, Nandy A, Ghisla S, Kim JJ Biochemistry. 1996 Sep 24;35(38):12412-20. PMID:8823176[16]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Matsubara Y, Narisawa K, Miyabayashi S, Tada K, Coates PM, Bachmann C, Elsas LJ 2nd, Pollitt RJ, Rhead WJ, Roe CR. Identification of a common mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency. Biochem Biophys Res Commun. 1990 Aug 31;171(1):498-505. PMID:2393404
- ↑ Yokota I, Indo Y, Coates PM, Tanaka K. Molecular basis of medium chain acyl-coenzyme A dehydrogenase deficiency. An A to G transition at position 985 that causes a lysine-304 to glutamate substitution in the mature protein is the single prevalent mutation. J Clin Invest. 1990 Sep;86(3):1000-3. PMID:2394825 doi:http://dx.doi.org/10.1172/JCI114761
- ↑ Kelly DP, Whelan AJ, Ogden ML, Alpers R, Zhang ZF, Bellus G, Gregersen N, Dorland L, Strauss AW. Molecular characterization of inherited medium-chain acyl-CoA dehydrogenase deficiency. Proc Natl Acad Sci U S A. 1990 Dec;87(23):9236-40. PMID:2251268
- ↑ Yokota I, Coates PM, Hale DE, Rinaldo P, Tanaka K. Molecular survey of a prevalent mutation, 985A-to-G transition, and identification of five infrequent mutations in the medium-chain Acyl-CoA dehydrogenase (MCAD) gene in 55 patients with MCAD deficiency. Am J Hum Genet. 1991 Dec;49(6):1280-91. PMID:1684086
- ↑ Gregersen N, Andresen BS, Bross P, Winter V, Rudiger N, Engst S, Christensen E, Kelly D, Strauss AW, Kolvraa S, et al.. Molecular characterization of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency: identification of a lys329 to glu mutation in the MCAD gene, and expression of inactive mutant enzyme protein in E. coli. Hum Genet. 1991 Apr;86(6):545-51. PMID:1902818
- ↑ Blakemore AI, Singleton H, Pollitt RJ, Engel PC, Kolvraa S, Gregersen N, Curtis D. Frequency of the G985 MCAD mutation in the general population. Lancet. 1991 Feb 2;337(8736):298-9. PMID:1671131
- ↑ Andresen BS, Jensen TG, Bross P, Knudsen I, Winter V, Kolvraa S, Bolund L, Ding JH, Chen YT, Van Hove JL, et al.. Disease-causing mutations in exon 11 of the medium-chain acyl-CoA dehydrogenase gene. Am J Hum Genet. 1994 Jun;54(6):975-88. PMID:8198141
- ↑ Ziadeh R, Hoffman EP, Finegold DN, Hoop RC, Brackett JC, Strauss AW, Naylor EW. Medium chain acyl-CoA dehydrogenase deficiency in Pennsylvania: neonatal screening shows high incidence and unexpected mutation frequencies. Pediatr Res. 1995 May;37(5):675-8. PMID:7603790
- ↑ Brackett JC, Sims HF, Steiner RD, Nunge M, Zimmerman EM, deMartinville B, Rinaldo P, Slaugh R, Strauss AW. A novel mutation in medium chain acyl-CoA dehydrogenase causes sudden neonatal death. J Clin Invest. 1994 Oct;94(4):1477-83. PMID:7929823 doi:http://dx.doi.org/10.1172/JCI117486
- ↑ Andresen BS, Bross P, Udvari S, Kirk J, Gray G, Kmoch S, Chamoles N, Knudsen I, Winter V, Wilcken B, Yokota I, Hart K, Packman S, Harpey JP, Saudubray JM, Hale DE, Bolund L, Kolvraa S, Gregersen N. The molecular basis of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in compound heterozygous patients: is there correlation between genotype and phenotype? Hum Mol Genet. 1997 May;6(5):695-707. PMID:9158144
- ↑ Kuchler B, Abdel-Ghany AG, Bross P, Nandy A, Rasched I, Ghisla S. Biochemical characterization of a variant human medium-chain acyl-CoA dehydrogenase with a disease-associated mutation localized in the active site. Biochem J. 1999 Jan 15;337 ( Pt 2):225-30. PMID:9882619
- ↑ Yang BZ, Ding JH, Zhou C, Dimachkie MM, Sweetman L, Dasouki MJ, Wilkinson J, Roe CR. Identification of a novel mutation in patients with medium-chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2000 Mar;69(3):259-62. PMID:10767181 doi:10.1006/mgme.2000.2978
- ↑ Andresen BS, Dobrowolski SF, O'Reilly L, Muenzer J, McCandless SE, Frazier DM, Udvari S, Bross P, Knudsen I, Banas R, Chace DH, Engel P, Naylor EW, Gregersen N. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Epub 2001 May 8. PMID:11349232 doi:10.1086/320602
- ↑ Zschocke J, Schulze A, Lindner M, Fiesel S, Olgemoller K, Hoffmann GF, Penzien J, Ruiter JP, Wanders RJ, Mayatepek E. Molecular and functional characterisation of mild MCAD deficiency. Hum Genet. 2001 May;108(5):404-8. PMID:11409868
- ↑ Albers S, Levy HL, Irons M, Strauss AW, Marsden D. Compound heterozygosity in four asymptomatic siblings with medium-chain acyl-CoA dehydrogenase deficiency. J Inherit Metab Dis. 2001 Jun;24(3):417-8. PMID:11486912
- ↑ Lee HJ, Wang M, Paschke R, Nandy A, Ghisla S, Kim JJ. Crystal structures of the wild type and the Glu376Gly/Thr255Glu mutant of human medium-chain acyl-CoA dehydrogenase: influence of the location of the catalytic base on substrate specificity. Biochemistry. 1996 Sep 24;35(38):12412-20. PMID:8823176 doi:10.1021/bi9607867
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