The development of sexual organs in humans is still not completely understood at the molecular level, controlled through the chromosomal difference between men and women. Steroids related to sexual development can have a temporary or permanent effects. Androgens are the leading compounds differentiating between (among other sexual organs) the internal and external genitalia of men.
Next to the classical pathway of androgen synthesis (see [https://www.wikipathways.org/index.php/Pathway:WP4523]), alternative pathways are known, which make use of either selective expression patterns of isoenzymes or alternate enzymes. As an alternative, a socalled 'backdoor pathway', which can create dihydrotestosterone (DHT), skipping testosterone. Several enzymes between the classical and backdoor pathway are shared, however the later one utilises one unique enzyme, 3-alpha hydroxysteroid dehydrogenase 3 (gene: AKR1C2). Even though the relevance of this backdoor pathway for humans is not completely clear yet, mutations in the human AKR1C2 gene can lead to disordered sexual differentiation. This finding would indicate that both the classical and the alternative pathway are needed for normal development of male genitalia in humans.
For more information on androgens, see Hiort (2013 [https://www.ncbi.nlm.nih.gov/pubmed/23800242]), and for more information on the disease linked to this pathway, please visit Chapter 37 of the book of Blau (ISBN 3642403360 (978-3642403361)).dffbd0c2ad01a78f1da5aAka HSD3B2; 3 beta-hydroxysteroid dehydrogenase type IIResponsible protein found through Rhea (not part of Blau book)b24b21b21Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" [https://www.uniprot.org/uniprot/P16435]c2aac0fa0b21f1da5aFunction:"Conversion of pregnenolone and progesterone to their 17-alpha-hydroxylated products and subsequently to dehydroepiandrosterone (DHEA) and androstenedione. Catalyzes both the 17-alpha-hydroxylation and the 17,20-lyase reaction. Involved in sexual development during fetal life and at puberty" [https://www.uniprot.org/uniprot/P05093]e32d30e32Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" [https://www.uniprot.org/uniprot/P16435]Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" [https://www.uniprot.org/uniprot/P16435]Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" [https://www.uniprot.org/uniprot/P16435]Function:"This enzyme is required for electron transfer from NADP to cytochrome P450 in microsomes" [https://www.uniprot.org/uniprot/P16435]Responsible protein found through Rhea (not part of Blau book)ReducedReducedReducedReducedReducedOxidisedOxidisedOxidisedOxidisedOxidised**No Rhea availableb21d30e32cc7d66fedcc7ac0fa0Specific Rhea for this reaction is not available at the moment; added Rhea for compounds classes reaction**No Rhea availablecc7ac0fa0cc7fa0c80fcae64edab21fa8cc1a5afcab21edaf40cc7d66d50b21f1dff1acdb21f1d**No Rhea availableaa9a78f94d01**No Rhea availableb21a5ac80b21b21edaedaedaedacc7cc7f1da5a26545797PubMed26545797PubMedBiochemical analyses and molecular modeling explain the functional loss of 17β-hydroxysteroid dehydrogenase 3 mutant G133R in three Tunisian patients with 46, XY Disorders of Sex Development.J Steroid Biochem Mol Biol2016Engeli RTRhouma BBSager CPTsachaki MBirk JFakhfakh FKeskes LBelguith NOdermatt A7217084PubMedAdrenal mitochondrial cytochrome P-450scc. Cholesterol and adrenodoxin interactions at equilibrium and during turnover.J Biol Chem1981Hanukoglu ISpitsberg VBumpus JADus KMJefcoate CR10998348PubMedHuman 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones.Biochem J2000Penning TMBurczynski MEJez JMHung CFLin HKMa HMoore MPalackal NRatnam K1123350PubMedDihydrotestosterone formation in cultured human fibroblasts. Comparison of cells from normal subjects and patients with familial incomplete male pseudohermaphroditism, Type 2.J Biol Chem1975Wilson JD164477PubMedGenetic and hormonal control of male sexual differentiation.J Cell Physiol1975Goldstein JLWilson JDaltered isoprenoid biosynthetic pathwayPW:0000751Pathway Ontologydisease pathwayPW:0000013Pathway Ontologysteroid inherited metabolic disorderDOID:1701Disease11360992PubMedFurther characterization of human microsomal 3alpha-hydroxysteroid dehydrogenase.Arch Biochem Biophys2001Chetyrkin SVHu JGough WHDumaual NKedishvili NY26587646PubMedMechanistic Scrutiny Identifies a Kinetic Role for Cytochrome b5 Regulation of Human Cytochrome P450c17 (CYP17A1, P450 17A1).PLoS One2015Simonov ANHolien JKYeung JCNguyen ADCorbin CJZheng JKuznetsov VLAuchus RJConley AJBond AMParker MWRodgers RJMartin LL9452426PubMedCytochrome b5 augments the 17,20-lyase activity of human P450c17 without direct electron transfer.J Biol Chem1998Auchus RJLee TCMiller WL9783642403361ISBNPhysician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic DiseasesISBN 978-3-642-40337-82014Blau, NenadDuran, MarinusGibson, K. MichaelDionisi-Vici, Carlo2339109PubMedStructural and biochemical properties of cloned and expressed human and rat steroid 5 alpha-reductases.Proc Natl Acad Sci U S A1990Andersson SRussell DW21802064PubMedWhy boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.Am J Hum Genet201121802064PubMedWhy boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation.Am J Hum Genet2011Flück CEMeyer-Böni MPandey AVKempná PMiller WLSchoenle EJBiason-Lauber Asteroid hormone metabolic pathwayPW:0001305Pathway Ontology21586563PubMedHigh-yield expression of a catalytically active membrane-bound protein: human P450 oxidoreductase.Endocrinology2011Sandee DMiller WLtestosterone biosynthetic pathwayPW:0000778Pathway Ontology14640697PubMedBroad substrate specificity of human cytochrome P450 46A1 which initiates cholesterol degradation in the brain.Biochemistry2003Mast NNorcross RAndersson UShou MNakayama KBjorkhem IPikuleva IA26855069PubMedCharacterization of 5α-reductase activity and isoenzymes in human abdominal adipose tissues.J Steroid Biochem Mol Biol2016Fouad Mansour MPelletier MTchernof A19661994PubMedMeasurement of cytochrome P450 and NADPH-cytochrome P450 reductase.Nat Protoc2009Guengerich FPMartin MVSohl CDCheng Q23800242PubMedThe differential role of androgens in early human sex development.BMC Med2013Hiort O26668369PubMedUnveiling the crucial intermediates in androgen production.Proc Natl Acad Sci U S A2015Mak PJGregory MCDenisov IGSligar SGKincaid JR12917011PubMedExpanded substrate screenings of human and Drosophila type 10 17beta-hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile acid and steroid hormone metabolism: characterization of multifunctional 3alpha/7alpha/7beta/17beta/20beta/21-HSD.Biochem J2003Shafqat NMarschall HUFilling CNordling EWu XQBjörk LThyberg JMårtensson ESalim SJörnvall HOppermann U10898110PubMedBiochemical and pharmacogenetic dissection of human steroid 5 alpha-reductase type II.Pharmacogenetics2000Makridakis NMdi Salle EReichardt JK11329262PubMedDetermination of the redox properties of human NADPH-cytochrome P450 reductase.Biochemistry2001Munro AWNoble MARobledo LDaff SNChapman SKsteroid metabolic pathwayPW:0001303Pathway Ontology27339894PubMedMechanism of 17α,20-Lyase and New Hydroxylation Reactions of Human Cytochrome P450 17A1: 18O LABELING AND OXYGEN SURROGATE EVIDENCE FOR A ROLE OF A PERFERRYL OXYGEN.J Biol Chem2016Yoshimoto FKGonzalez EAuchus RJGuengerich FP25577493PubMedAldo-keto Reductase 1B15 (AKR1B15): a mitochondrial human aldo-keto reductase with activity toward steroids and 3-keto-acyl-CoA conjugates.J Biol Chem2015Weber SSalabei JKMöller GKremmer EBhatnagar AAdamski JBarski OA8075637PubMedMale pseudohermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid dehydrogenase 3.Nat Genet1994Geissler WMDavis DLWu LBradshaw KDPatel SMendonca BBElliston KOWilson JDRussell DWAndersson Saltered steroid biosynthetic pathwayPW:0001306Pathway Ontology240819PubMedDiminished 5alpha-reductase activity in extracts of fibroblasts cultured from patients with familial incomplete male pseudohermaphroditism, type 2.J Biol Chem1975Moore RJGriffin JEWilson JD17386955PubMedFunctional expression and characterisation of human cytochrome P45017alpha in Pichia pastoris.J Biotechnol2007Kolar NWSwart ACMason JISwart Psteroid hormone biosynthetic pathwayPW:0000040Pathway Ontology18707589PubMedEngineering, expression, and purification of "soluble" human cytochrome P45017alpha and its functional characterization.Biochemistry (Mosc)2008Pechurskaya TALukashevich OPGilep AAUsanov SA16216911PubMedAndrogen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 in mammalian and non-mammalian vertebrates: comparison of the human and the zebrafish enzyme.J Mol Endocrinol2005Mindnich RHaller FHalbach FMoeller GHrabé de Angelis MAdamski Jcholesterol metabolic pathwayPW:0001304Pathway Ontology11294878PubMedCharacterization of a novel type of human microsomal 3alpha -hydroxysteroid dehydrogenase: unique tissue distribution and catalytic properties.J Biol Chem2001Chetyrkin SVBelyaeva OVGough WHKedishvili NY21636783PubMedStructural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system.Proc Natl Acad Sci U S A2011Strushkevich NMacKenzie FCherkesova TGrabovec IUsanov SPark HW21159775PubMedStructural basis for three-step sequential catalysis by the cholesterol side chain cleavage enzyme CYP11A1.J Biol Chem2011Mast NAnnalora AJLodowski DTPalczewski KStout CDPikuleva IA26976652PubMedRole of cytochrome b5 in the modulation of the enzymatic activities of cytochrome P450 17α-hydroxylase/17,20-lyase (P450 17A1).J Steroid Biochem Mol Biol2017Bhatt MRKhatri YRodgers RJMartin LL1238395PubMedMass spectrometric study of the enzymatic conversion of cholesterol to (22R)-22-hydroxycholesterol, (20R,22R)-20,22-dihydroxycholesterol, and pregnenolone, and of (22R)-22-hydroxycholesterol to the lgycol and pregnenolone in bovine adrenocortical preparations. Mode of oxygen incorporation.J Biol Chem1975Burstein SMiddleditch BSGut M