{"doi":"10.1016/j.jsbmb.2020.105586","title":"Human dehydrogenase/reductase SDR family member 11 (DHRS11) and aldo-keto reductase 1C isoforms in comparison: Substrate and reaction specificity in the reduction of 11-keto-C19-steroids","abstract":null,"journal":"The Journal of Steroid Biochemistry and Molecular Biology","year":2020,"id":617746,"datarank":0.6152544159870232,"base_score":3.044522437723423,"endowment":3.044522437723423,"self_citation_contribution":0.4566783656585135,"citation_network_contribution":0.1585760503285097,"self_endowment_contribution":0.4566783656585135,"citer_contribution":0.1585760503285097,"corpus_percentile":null,"corpus_rank":null,"citation_count":20,"citer_count":10,"citers_with_citation_signal":6,"citers_with_endowment":6,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1593218,"name":"Yoshifumi Morikawa","orcid":null,"position":1,"is_corresponding":false},{"id":1593219,"name":"Yudai Kudo","orcid":null,"position":2,"is_corresponding":false},{"id":1593220,"name":"Koichi Suenami","orcid":null,"position":3,"is_corresponding":false},{"id":1593221,"name":"Toshiyuki Matsunaga","orcid":null,"position":4,"is_corresponding":false},{"id":1593222,"name":"Akira Ikari","orcid":null,"position":5,"is_corresponding":false},{"id":781260,"name":"Akira Hara","orcid":"0000-0002-5554-8060","position":6,"is_corresponding":false},{"id":162593,"name":"Satoshi Endo","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Human dehydrogenase/reductase SDR family member 11 (DHRS11) and aldo-keto reductase 1C isoforms in comparison: Substrate and reaction specificity in the reduction of 11-keto-C19-steroids","abstract":"Recent studies have shown that an adrenal steroid 11β-hydroxy-4-androstene-3,17-dione serves as the precursor to androgens, 11-ketotestosterone and 11-ketodihydrotestosterone (11KDHT). The biosynthetic pathways include the reduction of 3- and 17-keto groups of the androgen precursors 11-keto-C19-steroids, which has been reported to be mediated by three human enzymes; aldo-keto reductase (AKR)1C2, AKR1C3 and 17β-hydroxysteroid dehydrogenase (HSD) type-3. To explore the contribution of the enzymes in the reductive metabolism, we kinetically compared the substrate specificity for 11-keto-C19-steroids among purified recombinant preparations of four AKRs (1C1, 1C2,1C3 and 1C4) and DHRS11, which shows 17β-HSD activity. Although AKR1C1 did not reduce the 11-keto-C19-steroids, AKR1C3 and DHRS11 reduced 17-keto groups of 11-keto-4-androstene-3,17-dione, 11-keto-5α-androstane-3,17-dione (11K-Adione) and 11-ketoandrosterone with Km values of 5-28 μM. The 3-keto groups of 11KDHT and 11K-Adione were reduced by AKR1C4 (Km 1 μM) more efficiently than by AKR1C2 (Km 5 and 8 μM, respectively). GC/MS analysis of the products showed that DHRS11 acts as 17β-HSD, and that AKR1C2 and AKR1C4 are predominantly 3α-HSDs, but formed a minor 3β-metabolite from 11KDHT. Since DHRS11 was thus newly identified as 11-keto-C19-steroid reductase, we also investigated its substrate-binding mode by molecular docking and site-directed mutagenesis of Thr163 and Val200, and found the following structural features: 1). There is a space that accommodates the 11-keto group of the 11-keto-C19-steroids in the substrate-binding site. 2) Val200 is a critical determinant for exhibiting the strict 17β-HSD activity of the enzyme, because the Val200Leu mutation resulted in both significant impairment of the 17β-HSD activity and emergence of 3β-HSD activity towards 5α-androstanes including 11KDHT.","is_dataset_classified":null,"base_score":3.044522437723423,"endowment":3.044522437723423,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"31926269","pmcid":null,"openalex_id":"https://openalex.org/W3000564706","authors":[],"funders":[],"total_grants":0,"fwci":1.694,"citation_percentile":0.85192021,"influential_citations":0,"citation_trend":[{"year":2020,"count":1},{"year":2021,"count":4},{"year":2022,"count":4},{"year":2023,"count":4},{"year":2024,"count":1},{"year":2025,"count":2},{"year":2026,"count":4}],"oa_status":"closed","license":"https://www.elsevier.com/legal/tdmrep-license","oa_locations":[{"url":"https://api.elsevier.com/content/article/PII:S0960076019306971?httpAccept=text/xml","host_type":"publisher"},{"url":"https://api.elsevier.com/content/article/PII:S0960076019306971?httpAccept=text/plain","host_type":"publisher"},{"url":"https://doi.org/10.1016/j.jsbmb.2020.105586","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/31926269","host_type":"repository"}],"fields_of_study":["Hormonal and reproductive studies","Aldose Reductase and Taurine","Sexual Differentiation and Disorders","17-Hydroxysteroid Dehydrogenases","20-Hydroxysteroid Dehydrogenases","Aldo-Keto Reductase Family 1 Member C3","Aldo-Keto Reductases","Androgens","Biosynthetic Pathways","Humans","Molecular Docking Simulation","Oxidoreductases","Protein Isoforms","Steroids","Substrate Specificity","Testosterone"],"mesh_terms":["Aldo-Keto Reductases","Aldo-Keto Reductase Family 1 Member C3","Androgens","Humans","Oxidoreductases","Steroids","Substrate Specificity","Testosterone","17-Hydroxysteroid Dehydrogenases","20-Hydroxysteroid Dehydrogenases","Protein Isoforms","Biosynthetic Pathways","Molecular Docking Simulation"],"keywords":["Reductase","Aldo-keto reductase","Dehydrogenase","Enzyme","Steroid","Biochemistry","Metabolite","Chemistry","Stereochemistry","Androgen","Biology","Hormone","11-Oxygenated androgen","DHRS11","GC/MS","Hydroxysteroid dehydrogenase","Specificity determinant"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Clean water and sanitation"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T02:31:19.394577Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}