Unique multifunctional HSD17B4 gene product: 17beta-hydroxysteroid dehydrogenase 4 and D-3-hydroxyacyl-coenzyme A dehydrogenase/hydratase involved in Zellweger syndrome

Abstract

Six types of human 17 -hydroxysteroid dehydrogenases catalyzing the conversion of estrogens and androgens at position C17 have been identified so far. The peroxisomal 17 -hydroxysteroid dehydrogenase type 4 (17 -HSD 4, gene name HSD17B4) catalyzes the oxidation of estradiol with high preference over the reduction of estrone. The highest levels of 17 -HSD 4 mRNA transcription and specific activity are found in liver and kidney followed by ovary and testes. A 3 kb mRNA codes for an 80 kDa (737 amino acids) protein featuring domains which are not present in the other 17 -HSDs. The N-terminal domain of 17 -HSD 4 reveals only 25% amino acid similarity with the other types of 17 -HSDs. The 80 kDa protein is N-terminally cleaved to a 32 kDa enzymatically active fragment. Both the 80 kDa and the N-terminal 32 kDa (amino acids 1-323) protein are able to perform the dehydrogenase reaction not only with steroids at the C17 position but also with -3-hydroxyacyl-coenzyme A (CoA). The enzyme is not active with -stereoisomers. The central part of the 80 kDa protein (amino acids 324-596) catalyzes the 2-enoyl-acyl-CoA hydratase reaction with high efficiency. The C-terminal part of the 80 kDa protein (amino acids 597-737) facilitates the transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The HSD17B4 gene is stimulated by progesterone, and ligands of PPAR (peroxisomal proliferator activated receptor alpha) such as clofibrate, and is down-regulated by phorbol esters. Mutations in the HSD17B4 lead to a fatal form of Zellweger syndrome.

Crystal structure of the liganded SCP-2-like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 Å resolution 1 1Edited by R. Huber

“…The SCP-2L of MFE-2 and SCP-2/SCPX are encoded by gene regions with similar intronexon structure, suggesting that these multidomain proteins have acquired the SCP-2 or SCP-2L by fusing genetic material from the same origin. 9,18,19 Mice lacking SCP-2/SCPX developed a peroxisomal b-oxidation de®ciency-like phenotype, 20 supporting the suggestion that SCP-2/SCPX function as carriers for fatty acyl-CoAs rather than for sterols as initially anticipated. 21,22 In addition, SCP-2 was shown to interact with acyl-CoA oxidase, 23 suggesting that SCP-2 may function in the transfer of fatty acyl-CoA derivatives to acyl-CoA oxidase.…”

“…4 ± 8 Analysis of accumulating metabolites in patients with MFE-2 de®ciency and`k nock-out'' mice, together with enzymatic properties observed in vitro, suggest that the physiological role of mammalian MFE-2 is the peroxisomal b-oxidation of very-long-chain fatty acids and 2-methyl-branched-chain fatty acids as well as di-and trihydroxycholestanoic acids. 9,10 (3R)-hydroxyacyl-CoA dehydrogenase, which catalyzes the third reaction of the b-oxidation pathway, is located to the N terminus of MFE-2, followed by the trans-2-enoyl-CoA hydratase 2 domain, responsible for the second reaction. Both domains were ®rst identi®ed experimentally in yeast MFE-2.…”

Steroid metabolism in cnidarians: Insights from Nematostella vectensis

“…Hsd17B8 homologs are present in both protostomes and deuterostomes, and the sequences are surprisingly well-conserved between humans and C. elegans (Baker, 2001). Both 17β-HSD4 and 8 are predominantly oxidative enzymes that can convert estradiol to estrone in the presence of NAD + (de Launoit and Adamski, 1999;Luu-The, 2001). Structural, functional, and evolutionary analyses of the Hsd17b4 clade have indicated that the primary substrates for 17β-HSD 4 enzymes are long-and branched-chain fatty acids, and 17β-HSD 4s most likely play only a minor physiological role in steroid metabolism (reviewed by Breitling et al, 2001).…”

Perrault Sendromunun genetik patogenezi

“…Previously, partial deficiency of the mitochondrial enzyme cytochrome c oxidase and muscle coenzyme Q10 (CoQ10) deficiency was reported in cases with PS (4,5). Recently, mutations in 17 beta-hydroxysteroid dehydrogenase type 4 (also known as D-bifunctional protein (HSD17B4/DBP)) which is also involved in Zellweger syndrome, one of three leukodystrophies and mitochondrial histidyl tRNA synthetase (HARS2) also implicated, in the leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL), have been proposed as the genetic causes of PS (6)(7)(8). The "ovarioleukodystrophies" comprise a group of rare leukodystrophies associated with POI.…”