{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T21:20:10Z","timestamp":1773696010362,"version":"3.50.1"},"reference-count":49,"publisher":"Elsevier BV","issue":"35","license":[{"start":{"date-parts":[[2019,8,1]],"date-time":"2019-08-01T00:00:00Z","timestamp":1564617600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2020,8,31]],"date-time":"2020-08-31T00:00:00Z","timestamp":1598832000000},"content-version":"vor","delay-in-days":396,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research, National Institutes of Health (OER)","doi-asserted-by":"publisher","award":["R01 GM118122"],"award-info":[{"award-number":["R01 GM118122"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006955","name":"HHS | NIH | Office of Extramural Research, National Institutes of Health (OER)","doi-asserted-by":"publisher","award":["T32 ES007028"],"award-info":[{"award-number":["T32 ES007028"]}],"id":[{"id":"10.13039\/100006955","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["jbc.org","elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Biological Chemistry"],"published-print":{"date-parts":[[2019,8]]},"DOI":"10.1074\/jbc.ra119.009830","type":"journal-article","created":{"date-parts":[[2019,7,12]],"date-time":"2019-07-12T02:44:01Z","timestamp":1562899441000},"page":"12975-12991","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":32,"title":["Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone"],"prefix":"10.1016","volume":"294","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0237-786X","authenticated-orcid":false,"given":"Michael J.","family":"Reddish","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7458-3048","authenticated-orcid":false,"given":"F. Peter","family":"Guengerich","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1074\/jbc.RA119.009830_bib1","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1021\/tx500444e","article-title":"Survey of human oxidoreductases and cytochrome P450 enzymes involved in the metabolism of xenobiotic and natural chemicals","volume":"28","author":"Rendic","year":"2015","journal-title":"Chem. Res. Toxicol"},{"key":"10.1074\/jbc.RA119.009830_bib2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/acs.chemrestox.6b00226","article-title":"Intersection of the roles of cytochrome P450 enzymes with xenobiotic and endogenous substrates: relevance to toxicity and drug interactions","volume":"30","author":"Guengerich","year":"2017","journal-title":"Chem. Res. Toxicol"},{"key":"10.1074\/jbc.RA119.009830_bib3","series-title":"Cytochrome P450: Structure, Mechanism, and Biochemistry","first-page":"523","article-title":"Human cytochrome P450 enzymes","author":"Guengerich","year":"2015"},{"key":"10.1074\/jbc.RA119.009830_bib4","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.1210\/jcem.87.8.8763","article-title":"Compound heterozygous mutations in the cholesterol side-chain cleavage enzyme gene (CYP11A) cause congenital adrenal insufficiency in humans","volume":"87","author":"Katsumata","year":"2002","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib5","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1210\/jc.2007-2330","article-title":"Severe combined adrenal and gonadal deficiency caused by novel mutations in the cholesterol side chain cleavage enzyme, P450scc","volume":"93","author":"Kim","year":"2008","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib6","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1210\/jc.2009-0651","article-title":"Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11\u03b2-hydroxylase deficiency","volume":"95","author":"Parajes","year":"2010","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib7","doi-asserted-by":"crossref","first-page":"4996","DOI":"10.1073\/pnas.89.11.4996","article-title":"Mutations in the human CYP11B2 (aldosterone synthase) gene causing corticosterone methyloxidase II deficiency","volume":"89","author":"Pascoe","year":"1992","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.RA119.009830_bib8","first-page":"4156","article-title":"Isolated aldosterone synthase deficiency caused by simultaneous E198D and V386A mutations in the CYP11B2 gene","volume":"83","author":"Portrat-Doyen","year":"1998","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.jsbmb.2016.02.002","article-title":"Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic","volume":"165","author":"Auchus","year":"2017","journal-title":"J. Steroid Biochem. Mol. Biol"},{"key":"10.1074\/jbc.RA119.009830_bib10","doi-asserted-by":"crossref","first-page":"S18","DOI":"10.1177\/1071557600007001S07","article-title":"Genetic mutations resulting in loss of aromatase activity in humans and mice","volume":"7","author":"Simpson","year":"2000","journal-title":"J. Soc. Gynecol. Investig"},{"key":"10.1074\/jbc.RA119.009830_bib11","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1210\/me.2012-1287","article-title":"Structural insights into aldosterone synthase substrate specificity and targeted inhibition","volume":"27","author":"Strushkevich","year":"2013","journal-title":"Mol. Endocrinol"},{"key":"10.1074\/jbc.RA119.009830_bib12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jsbmb.2012.03.002","article-title":"Human aldosterone synthase: recombinant expression in E. coli and purification enables a detailed biochemical analysis of the protein on the molecular level","volume":"132","author":"Hobler","year":"2012","journal-title":"J. Steroid Biochem. Mol. Biol"},{"key":"10.1074\/jbc.RA119.009830_bib13","doi-asserted-by":"crossref","first-page":"957","DOI":"10.4158\/EP14551.RA","article-title":"Selective hypoaldosteronism: a review","volume":"21","author":"Wilczynski","year":"2015","journal-title":"Endocr. Pract"},{"key":"10.1074\/jbc.RA119.009830_bib14","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1210\/jcem.86.11.7925","article-title":"Cardiac steroidogenesis in the normal and failing heart","volume":"86","author":"Young","year":"2001","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib15","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1021\/jm0492397","article-title":"Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes\/\u2212indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase","volume":"48","author":"Ulmschneider","year":"2005","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib16","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1097\/HJH.0b013e328363570c","article-title":"Aldosterone synthase inhibition for the treatment of hypertension and the derived mechanistic requirements for a new therapeutic strategy","volume":"31","author":"Schumacher","year":"2013","journal-title":"J. Hypertens"},{"key":"10.1074\/jbc.RA119.009830_bib17","doi-asserted-by":"crossref","first-page":"8028","DOI":"10.1074\/jbc.271.14.8028","article-title":"Engineering a mineralocorticoid- to a glucocorticoid-synthesizing cytochrome P450","volume":"271","author":"B\u00f6ttner","year":"1996","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib18","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/nsb0197-32","article-title":"The amino acid substitutions Ser288Gly and Val320Ala convert the cortisol producing enzyme, CYP11B1, into an aldosterone producing enzyme","volume":"4","author":"Curnow","year":"1997","journal-title":"Nat. Struct. Biol"},{"key":"10.1074\/jbc.RA119.009830_bib19","first-page":"3996","article-title":"Recombinant CYP11B genes encode enzymes that can catalyze conversion of 11-deoxycortisol to cortisol, 18-hydroxycortisol, and 18-oxocortisol","volume":"83","author":"Mulatero","year":"1998","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib20","doi-asserted-by":"crossref","first-page":"8097","DOI":"10.1021\/bi9802768","article-title":"Kinetic studies on bovine cytochrome P45011\u03b2 catalyzing successive reactions from deoxycorticosterone to aldosterone","volume":"37","author":"Imai","year":"1998","journal-title":"Biochemistry"},{"key":"10.1074\/jbc.RA119.009830_bib21","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.jsbmb.2018.03.003","article-title":"Catalytic modulation of human cytochromes P450 17A1 and P450 11B2 by phospholipid","volume":"181","author":"Peng","year":"2018","journal-title":"J. Steroid Biochem. Mol. Biol"},{"key":"10.1074\/jbc.RA119.009830_bib22","doi-asserted-by":"crossref","first-page":"8054","DOI":"10.1021\/acs.jmedchem.5b00851","article-title":"Discovery of 4-aryl-5,6,7,8-tetrahydroisoquinolines as potent, selective, and orally active aldosterone synthase (CYP11B2) inhibitors: in vivo evaluation in rodents and cynomolgus monkeys","volume":"58","author":"Martin","year":"2015","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib23","doi-asserted-by":"crossref","first-page":"8031","DOI":"10.1074\/jbc.M109.088039","article-title":"Oxidation of N-nitrosoalkylamines by human cytochrome P450 2A6: sequential oxidation to aldehydes and carboxylic acids and analysis of reaction steps","volume":"285","author":"Chowdhury","year":"2010","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib24","doi-asserted-by":"crossref","first-page":"9995","DOI":"10.1021\/bi301092c","article-title":"Oxidation of methyl and ethyl nitrosamines by cytochrome P450 2E1 and 2B1","volume":"51","author":"Chowdhury","year":"2012","journal-title":"Biochemistry"},{"key":"10.1074\/jbc.RA119.009830_bib25","doi-asserted-by":"crossref","first-page":"17734","DOI":"10.1074\/jbc.M110.123711","article-title":"Kinetic analysis of the three-step steroid aromatase reaction of human cytochrome P450 19A1","volume":"285","author":"Sohl","year":"2010","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib26","first-page":"113","article-title":"Spectral studies of drug interaction with hepatic microsomal cytochrome","volume":"3","author":"Schenkman","year":"1967","journal-title":"Mol. Pharmacol"},{"key":"10.1074\/jbc.RA119.009830_bib27","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1002\/hlca.19540370423","article-title":"Aldosteron. Isolierung und eigenschaften. \u00dcber bestandteile der nebennierenrinde und verwandte stoffe. 91. Mitteilung","volume":"37","author":"Simpson","year":"1954","journal-title":"Helv. Chim. Acta"},{"key":"10.1074\/jbc.RA119.009830_bib28","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/BF02158515","article-title":"Konstitution des aldosterons, des neuen mineralocorticoids","volume":"10","author":"Simpson","year":"1954","journal-title":"Experientia"},{"key":"10.1074\/jbc.RA119.009830_bib29","doi-asserted-by":"crossref","first-page":"5171","DOI":"10.1016\/S0040-4020(99)00187-8","article-title":"A convenient synthesis of 18-hydroxycorticosterone and 18-hydroxy-11-desoxycorticosterone via stereospecific hypoiodination of 20-hydroxysteroids","volume":"55","author":"Boudi","year":"1999","journal-title":"Tetrahedron"},{"key":"10.1074\/jbc.RA119.009830_bib30","doi-asserted-by":"crossref","first-page":"1178","DOI":"10.1016\/j.bbadis.2009.10.017","article-title":"The role of 11\u03b2-hydroxysteroid dehydrogenase type 2 in human hypertension","volume":"1802","author":"Ferrari","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1074\/jbc.RA119.009830_bib31","doi-asserted-by":"crossref","first-page":"4320","DOI":"10.1021\/ja00300a041","article-title":"Complex isomerization of ketoses: a carbon-13 NMR study of the base-catalyzed ring-opening and ring-closing rates of d-fructose isomers in aqueous solution","volume":"107","author":"Goux","year":"1985","journal-title":"J. Am. Chem. Soc"},{"key":"10.1074\/jbc.RA119.009830_bib32","doi-asserted-by":"crossref","first-page":"5749","DOI":"10.1021\/jm100317b","article-title":"Replacement of imidazolyl by pyridyl in biphenylmethylenes results in selective CYP17 and dual CYP17\/CYP11B1 inhibitors for the treatment of prostate cancer","volume":"53","author":"Hu","year":"2010","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib33","doi-asserted-by":"crossref","first-page":"6101","DOI":"10.1021\/jm400484p","article-title":"Highly potent and selective nonsteroidal dual inhibitors of CYP17\/CYP11B2 for the treatment of prostate cancer to reduce risks of cardiovascular diseases","volume":"56","author":"Pinto-Bazurco Mendieta","year":"2013","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib34","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1021\/acsmedchemlett.5b00048","article-title":"Discovery of triazole CYP11B2 inhibitors with in vivo activity in Rhesus monkeys","volume":"6","author":"Hoyt","year":"2015","journal-title":"ACS Med. Chem. Lett"},{"key":"10.1074\/jbc.RA119.009830_bib35","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1021\/acs.jmedchem.5b00079","article-title":"Novel pyridyl substituted 4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolines as potent and selective aldosterone synthase inhibitors with improved in vitro metabolic stability","volume":"58","author":"Hu","year":"2015","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib36","doi-asserted-by":"crossref","first-page":"2468","DOI":"10.1021\/acs.jmedchem.5b01609","article-title":"Exploiting the chromone scaffold for the development of inhibitors of corticosteroid biosynthesis","volume":"59","author":"Gobbi","year":"2016","journal-title":"J. Med. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib37","doi-asserted-by":"crossref","first-page":"13168","DOI":"10.1074\/jbc.M117.794917","article-title":"Kinetic processivity of the two-step oxidations of progesterone and pregnenolone to androgens by human cytochrome P450 17A1","volume":"292","author":"Gonzalez","year":"2017","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib38","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1210\/jc.2011-2384","article-title":"18-Hydroxycorticosterone, 18-hydroxycortisol, and 18-oxocortisol in the diagnosis of primary aldosteronism and its subtypes","volume":"97","author":"Mulatero","year":"2012","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib39","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1210\/jcem-60-1-67","article-title":"The prediction of anatomical morphology of primary aldosteronism using serum 18-hydroxycorticosterone levels","volume":"60","author":"Kem","year":"1985","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib40","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1210\/jcem-66-1-181","article-title":"Dose-response relationships between plasma adrenocorticotropin (ACTH), cortisol, aldosterone, and 18-hydroxycorticosterone after injection of ACTH-(1\u201339) or human corticotropin-releasing hormone in man","volume":"66","author":"Oelkers","year":"1988","journal-title":"J. Clin. Endocrinol. Metab"},{"key":"10.1074\/jbc.RA119.009830_bib41","doi-asserted-by":"crossref","first-page":"12124","DOI":"10.1021\/jacs.6b04437","article-title":"Isotope-labeling studies support the electrophilic compound I iron active species, FeO3+, for the carbon\u2013carbon bond cleavage reaction of the cholesterol side-chain cleavage enzyme, cytochrome P450 11A1","volume":"138","author":"Yoshimoto","year":"2016","journal-title":"J. Am. Chem. Soc"},{"key":"10.1074\/jbc.RA119.009830_bib42","doi-asserted-by":"crossref","first-page":"5597","DOI":"10.1073\/pnas.88.13.5597","article-title":"Expression and enzymatic activity of recombinant cytochrome P450 17\u03b1-hydroxylase in Escherichia coli","volume":"88","author":"Barnes","year":"1991","journal-title":"Proc. Natl. Acad. Sci. U.S.A"},{"key":"10.1074\/jbc.RA119.009830_bib43","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1016\/S0021-9258(20)82244-3","article-title":"The carbon monoxide-binding pigment of liver microsomes: I. Evidence for its hemoprotein nature","volume":"239","author":"Omura","year":"1964","journal-title":"J. Biol. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib44","series-title":"Hayes' Principles and Methods of Toxicology","first-page":"1905","article-title":"Analysis and characterization of enzymes and nucleic acids relevant to toxicology","author":"Guengerich","year":"2014"},{"key":"10.1074\/jbc.RA119.009830_bib45","doi-asserted-by":"crossref","first-page":"16","DOI":"10.3762\/bjoc.15.2","article-title":"New standards for collecting and fitting steady state kinetic data","volume":"15","author":"Johnson","year":"2019","journal-title":"Beilstein J. Org. Chem"},{"key":"10.1074\/jbc.RA119.009830_bib46","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1111\/j.1476-5381.2009.00604.x","article-title":"Ligand binding assays at equilibrium: validation and interpretation","volume":"161","author":"Hulme","year":"2010","journal-title":"Br. J. Pharmacol"},{"key":"10.1074\/jbc.RA119.009830_bib47","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1021\/acs.jchemed.6b00629","article-title":"Linear or nonlinear least-squares analysis of kinetic data?","volume":"94","author":"Perrin","year":"2017","journal-title":"J. Chem. Educ"},{"key":"10.1074\/jbc.RA119.009830_bib48","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.ab.2008.12.024","article-title":"Global Kinetic Explorer: a new computer program for dynamic simulation and fitting of kinetic data","volume":"387","author":"Johnson","year":"2009","journal-title":"Anal. Biochem"},{"key":"10.1074\/jbc.RA119.009830_bib49","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ab.2008.12.025","article-title":"FitSpace Explorer: an algorithm to evaluate multidimensional parameter space in fitting kinetic data","volume":"387","author":"Johnson","year":"2009","journal-title":"Anal. Biochem"}],"container-title":["Journal of Biological Chemistry"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002192582043234X?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S002192582043234X?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1074\/jbc.RA119.009830","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T12:35:57Z","timestamp":1641299757000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S002192582043234X"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8]]},"references-count":49,"journal-issue":{"issue":"35","published-print":{"date-parts":[[2019,8]]}},"alternative-id":["S002192582043234X"],"URL":"https:\/\/doi.org\/10.1074\/jbc.ra119.009830","relation":{},"ISSN":["0021-9258"],"issn-type":[{"value":"0021-9258","type":"print"}],"subject":[],"published":{"date-parts":[[2019,8]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Human cytochrome P450 11B2 produces aldosterone by a processive mechanism due to the lactol form of the intermediate 18-hydroxycorticosterone","name":"articletitle","label":"Article Title"},{"value":"Journal of Biological Chemistry","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1074\/jbc.RA119.009830","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2019 Reddish and Guengerich.","name":"copyright","label":"Copyright"}]}}