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Characterization of a novel variant (S145C/L311V) of 3 ??-hydroxysteroid/dihydrodiol dehydrogenase in human liver
Abstract
Human liver 3alpha-hydroxysteroid/dihydrodiol dehydrogenase (DD) is involved in the metabolism of steroid hormones and polycyclic aromatic hydrocarbons, and is also responsible for the reduction of ketone-containing drugs. To account for the interindividual difference in the activity, we isolated and characterized clones for the human liver enzymes. The sequence of the cDNA clone coding for the variant differed from that coding for the wild-type DD by two nucleotides (substitutions of C with G at positions 434 and 931) which caused two amino acid replacements, Ser145 to Cys (S145C) and Leu311 to Val (L311V). The heterologous expression of the variant mRNA was confirmed in four of 31 liver samples from Japanese by an allele-specific polymerase chain reaction. The effects of the mutations on the catalytic properties were examined with the recombinant enzymes expressed in Escherichia coli. The introduction of S145C/L311V double mutations resulted in three- to five-fold decreased activities for xenobiotic and steroidal substrates, whereas no significant change was observed by an introduction of the S145C mutation alone. The results substantiate the existence of polymorphic forms for human liver DD, and also suggest the importance of the residue at position 311 for substrate binding to the enzyme.
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The NIM rs17134592 alters leucine to valine (L311V), which, in combination with the tightly linked non-synonymous variant rs3829125 (S145C) in the same gene, has been shown to confer a three- to fivefold reduction in catalytic activity of the corresponding enzyme in human liver.
“This NIM alters leucine to valine (L311V), which, in combination with the tightly linked non-synonymous variant rs3829125 (S145C) in the same gene, have been shown to confer a three- to fivefold reduction in catalytic activity of the corresponding enzyme (3-alpha hydroxysteroid dehydrogenase) in human liver (Kume et al., 1999).”
From The lingering effects of Neanderthal introgression on human complex traits (2023) · cites this paper as Kume et al., 1999
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Metadata
- Authors
- Kume, T., Iwasa, H., Shiraishi, H., Yokoi, T., Nagashima, K., Otsuka, M., Terada, T., Takagi, T., Hara, A., & Kamataki, T.
- Affiliations
- Gifu Pharmaceutical University (JP)
- Venue
- Pharmacogenetics
- Published
- 1999-12
- Volume
- 9
- Issue
- 6
- Pages
- 763-772
- ISSN
- 0960-314X (ISSN-L)
- OpenAlex
- W2071878626
- Cited by
- 27
- References
- 0
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2022: 1 · 2021: 3 · 2019: 1 · 2017: 2 · 2016: 2
- FWCI
- 0.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacogenetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- CYP2B6, amino acid substitutions, enzyme activity, substrate binding, steroid hormone metabolism, polycyclic aromatic hydrocarbon metabolism, ketone reduction, interindividual variability, recombinant enzyme expression
- MeSH terms
- Base Sequence, Cloning, Molecular, Humans, Liver, Molecular Sequence Data, Oxidoreductases, Recombinant Proteins, DNA, Complementary
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