| Structural highlights
1f14 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Related: | 3had, 1f12, 1f17, 1f0y |
| Activity: | 3-hydroxyacyl-CoA dehydrogenase, with EC number 1.1.1.35 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Disease
[HCDH_HUMAN] Defects in HADH are the cause of 3-alpha-hydroxyacyl-CoA dehydrogenase deficiency (HADH deficiency) [MIM:231530]. HADH deficiency is a metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death. Defects in HADH are the cause of familial hyperinsulinemic hypoglycemia type 4 (HHF4) [MIM:609975]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. It causes nesidioblastosis, a diffuse abnormality of the pancreas in which there is extensive, often disorganized formation of new islets. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. HHF4 should be easily recognizable by analysis of acylcarnitine species and that this disorder responds well to treatment with diazoxide. It provides the first 'experiment of nature' that links impaired fatty acid oxidation to hyperinsulinism and that provides support for the concept that a lipid signaling pathway is implicated in the control of insulin secretion.[1]
Function
[HCDH_HUMAN] Plays an essential role in the mitochondrial beta-oxidation of short chain fatty acids. Exerts it highest activity toward 3-hydroxybutyryl-CoA.
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
l-3-Hydroxyacyl-CoA dehydrogenase reversibly catalyzes the conversion of l-3-hydroxyacyl-CoA to 3-ketoacyl-CoA concomitant with the reduction of NAD(+) to NADH as part of the beta-oxidation spiral. In this report, crystal structures have been solved for the apoenzyme, binary complexes of the enzyme with reduced cofactor or 3-hydroxybutyryl-CoA substrate, and an abortive ternary complex of the enzyme with NAD(+) and acetoacetyl-CoA. The models illustrate positioning of cofactor and substrate within the active site of the enzyme. Comparison of these structures with the previous model of the enzyme-NAD(+) complex reveals that although significant shifting of the NAD(+)-binding domain relative to the C-terminal domain occurs in the ternary and substrate-bound complexes, there are few differences between the apoenzyme and cofactor-bound complexes. Analysis of these models clarifies the role of key amino acids implicated in catalysis and highlights additional critical residues. Furthermore, a novel charge transfer complex has been identified in the course of abortive ternary complex formation, and its characterization provides additional insight into aspects of the catalytic mechanism of l-3-hydroxyacyl-CoA dehydrogenase.
Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase.,Barycki JJ, O'Brien LK, Strauss AW, Banaszak LJ J Biol Chem. 2000 Sep 1;275(35):27186-96. PMID:10840044[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, van den Berg IE. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J Clin Invest. 2001 Aug;108(3):457-65. PMID:11489939 doi:10.1172/JCI11294
- ↑ Barycki JJ, O'Brien LK, Strauss AW, Banaszak LJ. Sequestration of the active site by interdomain shifting. Crystallographic and spectroscopic evidence for distinct conformations of L-3-hydroxyacyl-CoA dehydrogenase. J Biol Chem. 2000 Sep 1;275(35):27186-96. PMID:10840044 doi:http://dx.doi.org/10.1074/jbc.M004669200
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