Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase

He, Xue‐Ying; Yang, Yutao; Schulz, Horst; Yang, Song‐Yu

doi:10.1042/bj3450139

Cited by 29 publications

(31 citation statements)

References 23 publications

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“…The biological relevance of some of these Fig. 1 The beta-oxidation of 2-methylbutyryl-CoA in the breakdown of isoleucine and possible other sources of C2-methylated short acyl-CoA compounds enzymatic activities has not been sufficiently proven; the alcohol dehydrogenase activity of HSD10 is marginal (He et al 2000). There is mounting evidence that HSD10 plays a role in the pathogenesis of several adult-onset neurodegenerative disorders, in particular, that through interaction with amyloid β HSD10 mediates mitochondrial toxicity in Alzheimer's disease (Lustbader et al 2004;Tieu et al 2004;Yan et al 1997;Yang et al 2011).…”

Section: Hsd10 and The Hsd17b10 Genementioning

confidence: 99%

HSD10 disease: clinical consequences of mutations in the HSD17B10 gene

Zschocke

2011

J of Inher Metab Disea

117

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The HSD17B10 gene is located on chromosome Xp11.2 and codes for a multifunctional protein called 17β-hydroxysteroid dehydrogenase type 10 (HSD10). This protein catalyzes the 2-methyl-3-hydroxybutyryl-CoA dehydrogenation (MHBD) reaction in isoleucine metabolism and is an essential component of mitochondrial RNase P required for the processing of mtDNA transcripts. HSD10 is required for normal mitochondrial maintenance, and complete loss of HSD10 is incompatible with life. Mutations in the HSD17B10 gene have been reported in 19 families. The classical infantile form of what is best named HSD10 disease is characterized by a period of more or less normal development in the first 6-18 months of life. Some patients showed transient metabolic derangement in the neonatal period, with good clinical recovery but often persistent lactate elevation. Usually from age 6-18 months affected boys show a progressive neurodegenerative disease course in conjunction with retinopathy and cardiomyopathy leading to death at age 2-4 years or later. A more severe presentation in the neonatal period with little neurological development, severe progressive cardiomyopathy, and early death, is denoted neonatal form. Juvenile and atypical/asymptomatic forms of HSD10 disease have been recognized. Heterozygous females often show non-progressive developmental delay and intellectual disability but may also be clinically normal. The pathogenesis is poorly understood but is unrelated to MHBD function. Diagnosis is based on typical abnormalities in urinary organic acid analysis and molecular studies. The same de novo mutation p.R130C was found in over half of patient families; it is associated with the infantile disease form. There is no effective treatment.

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Section: Hsd10 and The Hsd17b10 Genementioning

confidence: 99%

HSD10 disease: clinical consequences of mutations in the HSD17B10 gene

Zschocke

2011

J of Inher Metab Disea

117

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“…The erroneous localization of this protein to the endoplasmic reticulum [22] resulted in the designation of SCHAD as endoplasmic reticulum-associated amyloid-b-binding protein. However, it has been proven that SCHAD is localized in the mitochondrial matrix [1,[23][24][25][26][27][28][29]. This finding prompted a report that SCHAD and amyloid-b peptide are both responsible for the mitochondrial toxicity seen in AD [70].…”

Section: Relevance Of Schad To Mental Retardationmentioning

confidence: 99%

“…SCHAD is also known as type 10 17b-hydroxysteroid dehydrogenase (HSD10) [19,[23][24][25][26]. This human mitochondrial multifunctional enzyme [23][24][25][26][27][28] is a potential target for intervention of Alzheimer's disease (AD), Parkinson's disease (PD), infantile neurodegeneration, and other neural disorders [29][30][31][32]. The characteristics of HAD and SCHAD and their impact on human health and disease are further discussed in the following sections.…”

Section: Introductionmentioning

confidence: 99%

3‐Hydroxyacyl‐CoA dehydrogenase and short chain 3‐hydroxyacyl‐CoA dehydrogenase in human health and disease

Yang

Schulz

2005

The FEBS Journal

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3‐Hydroxyacyl‐CoA dehydrogenase (HAD) functions in mitochondrial fatty acid β‐oxidation by catalyzing the oxidation of straight chain 3‐hydroxyacyl‐CoAs. HAD has a preference for medium chain substrates, whereas short chain 3‐hydroxyacyl‐CoA dehydrogenase (SCHAD) acts on a wide spectrum of substrates, including steroids, cholic acids, and fatty acids, with a preference for short chain methyl‐branched acyl‐CoAs. Therefore, HAD should not be referred to as SCHAD. SCHAD is not a member of the HAD family, but instead, belongs to the short chain dehydrogenase/reductase superfamily. Previously reported cases of SCHAD deficiency are due to an inherited HAD deficiency. SCHAD, also known as 17β‐hydroxysteroid dehydrogenase type 10, is important in brain development and aging. Abnormal levels of SCHAD in certain brain regions may contribute to the pathogenesis of some neural disorders. The human SCHAD gene and its protein product, SCHAD, are potential targets for intervention in conditions, such as Alzheimer's disease, Parkinson's disease, and an X‐linked mental retardation, that may arise from the impaired degradation of branched chain fatty acid and isoleucine.

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“…9 In vitro, SDR5C1 also acts on other substrates, including branched short-chain fatty acids, hydroxysteroids, and sex hormones. [3][4][5][6]10,11 SDR5C1 deficiency causes a mitochondrial disorder known as 'HSD10 disease'. 7 Biochemical diagnosis of HSD10 disease has traditionally relied upon the detection of elevated metabolites from isoleucine breakdown, 12 which are the same metabolites elevated in patients with a-ketothiolase (AKT) deficiency.…”

Section: Introductionmentioning

confidence: 99%

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

et al. 2016

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(2016) A novel HSD17B10 mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression, RNA Biology, 13:5, 477-485, DOI: 10.1080/15476286.2016 ABSTRACTWe report a Caucasian boy with intractable epilepsy and global developmental delay. Whole-exome sequencing identified the likely genetic etiology as a novel p.K212E mutation in the X-linked gene HSD17B10 for mitochondrial short-chain dehydrogenase/reductase SDR5C1. Mutations in HSD17B10 cause the HSD10 disease, traditionally classified as a metabolic disorder due to the role of SDR5C1 in fatty and amino acid metabolism. However, SDR5C1 is also an essential subunit of human mitochondrial RNase P, the enzyme responsible for 5 0 -processing and methylation of purine-9 of mitochondrial tRNAs. Here we show that the p.K212E mutation impairs the SDR5C1-dependent mitochondrial RNase P activities, and suggest that the pathogenicity of p.K212E is due to a general mitochondrial dysfunction caused by reduction in SDR5C1-dependent maturation of mitochondrial tRNAs.

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Intrinsic alcohol dehydrogenase and hydroxysteroid dehydrogenase activities of human mitochondrial short-chain L-3-hydroxyacyl-CoA dehydrogenase

Cited by 29 publications

References 23 publications

HSD10 disease: clinical consequences of mutations in the HSD17B10 gene

HSD10 disease: clinical consequences of mutations in the HSD17B10 gene

3‐Hydroxyacyl‐CoA dehydrogenase and short chain 3‐hydroxyacyl‐CoA dehydrogenase in human health and disease

A novelHSD17B10mutation impairing the activities of the mitochondrial RNase P complex causes X-linked intractable epilepsy and neurodevelopmental regression

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