Metabolism of steroid hormones (Homo sapiens)

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17416, 29, 32, 36, 386114, 31269, 18, 23, 353, 3314, 31315, 283024, 373, 335, 22, 3839179, 18, 23, 35210, 209, 18, 23, 3538, 398, 215, 285, 2224, 3739257, 19, 27, 38171115, 3415, 34139, 3839131215, 349mitochondrial matrixLutropin CubilinDBPCalcidiol cytosollysosomal lumencytosolendoplasmic reticulum lumenDBPCalcidiol cholesterolSTAR DBPCalcidiol HSD17B1 dimer mitochondrial matrixDBPCalcidiol HSD11B1 dimer cholesterolStAR-related protein cytosolDBPvitamin D3 CubilinDBPCalcidiol Lutropin CUBNDBPcalcidiol H+NADP+EST17bNADP+HSD17B3NADP+CTLHCOOHCDL NADP+H+17alpha-hydroxypregnenoloneP4NADHAKR1B1pregn-5-ene-3,20-dioneCUBN H+H+CTAO2H2OHSD17B1 CYP21A2DBPCalcidiolVD3H+NADPHISCAL20alpha,22beta dihydroxycholesterolLHB NADHcholesterolNADP+H+LutropinH+H+NAD+POMCH2OCYP24A1CDL NADPHH2OCubilinDBPCalcidiolCUBN11-deoxycortisolVD3H+CYP17A1NADPHALDOHSD11B1 dimerH2ONADP+NADP+DBPvitamin D3CORTO2O2O2CGA 11-deoxycortisolNADPHNADPHNADP+MePeOHH2OH2OH+TESH2OCYP27B1CUBN H+CUBNDBPcalcidiolNADPHSRD5A1 or 2 or 3STARNADPHStAR-related cholesterol-binding proteinsPOMCO2NADPHNADP+O2NAD+cholesterolStAR-related proteinH2OCHOL NADP+GCPOMCDOCCDLCDLH+H+Pregnenolone17alpha-hydroxyprogesteroneO2GC CDL NADP+NADPHH+NADPHCDLCYP11A1HSD17B1 dimer22beta-hydroxycholesterolcholesterolSTARNADPHPOMCO2NADP+NADP+O2H2OH+H+LutropinE117alpha-hydroxyprogesteroneO218-hydroxycorticosteroneCORTO2NADPHPOMCISCALCYP11B1NADP+HSD11B1 CUBNO2NADP+CH3CHOP4E1CYP11B2CH3CHO4-Androstene-3, 17-dioneGC H2OCGA STAR NADPHDHTESTGC NADP+LRP2DHEAGC LHB cholesterol H+O2DOCO2NADPHPREGNADPHO2NADP+CubilinDBPCalcidiolH2ONADPH7-dehydrocholesterolH+CDL H2OH2Opregn-5-ene-3,20-dione-17-olCYP19A1H2OHSD2B1 or HSD3B2 dimerCUBN CYP2R1H+CORSTLGMNNADP+NADP+GC NADPHH+H2OH+NADPHCORVD3 NADPH


Description

Steroid hormones are synthesized primarily in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). All steroids are synthesized from cholesterol. Steroid hormone synthesis is largely regulated at the initial steps of cholesterol mobilization and transport into the mitochondrial matrix for conversion to pregnenolone. In the body, the fate of pregnenolone is tissue-specific: in the zona fasciculata of the adrenal cortex it is converted to cortisol, in the zona glomerulosa to aldosterone, and in the gonads to testosterone and then to estrone and estradiol. These pathways are outlined in the figure below, which also details the sites on the cholesterol molecule that undergo modification in the course of these reactions.

Vitamin D3 (cholecalciferol) is a steroid hormone that plays a role in regulating calcium and bone metabolism. The processes by which it is synthesized, modified, and transported in the body are annotated here. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=196071</div>

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Bibliography

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History

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CompareRevisionActionTimeUserComment
115089view17:04, 25 January 2021ReactomeTeamReactome version 75
113531view12:01, 2 November 2020ReactomeTeamReactome version 74
112729view16:13, 9 October 2020ReactomeTeamReactome version 73
101645view11:51, 1 November 2018ReactomeTeamreactome version 66
101181view21:38, 31 October 2018ReactomeTeamreactome version 65
100707view20:10, 31 October 2018ReactomeTeamreactome version 64
100257view16:56, 31 October 2018ReactomeTeamreactome version 63
99810view15:20, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99354view12:48, 31 October 2018ReactomeTeamreactome version 62
94495view09:01, 14 September 2017Mkutmonreactome version 61
87913view12:59, 25 July 2016RyanmillerOntology Term : 'classic metabolic pathway' added !
83163view10:14, 18 November 2015ReactomeTeamVersion54
81521view13:03, 21 August 2015ReactomeTeamVersion53
76990view08:28, 17 July 2014ReactomeTeamFixed remaining interactions
76695view12:06, 16 July 2014ReactomeTeamFixed remaining interactions
76021view10:08, 11 June 2014ReactomeTeamRe-fixing comment source
75730view11:20, 10 June 2014ReactomeTeamReactome 48 Update
75080view14:02, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74727view08:48, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
11-deoxycortisolMetaboliteCHEBI:28324 (ChEBI)
17alpha-hydroxypregnenoloneMetaboliteCHEBI:28750 (ChEBI)
17alpha-hydroxyprogesteroneMetaboliteCHEBI:17252 (ChEBI)
18-hydroxycorticosteroneMetaboliteCHEBI:16485 (ChEBI)
20alpha,22beta dihydroxycholesterolMetaboliteCHEBI:1294 (ChEBI)
22beta-hydroxycholesterolMetaboliteCHEBI:1301 (ChEBI)
4-Androstene-3, 17-dioneMetaboliteCHEBI:16422 (ChEBI)
7-dehydrocholesterolMetaboliteCHEBI:17759 (ChEBI)
AKR1B1ProteinP15121 (Uniprot-TrEMBL)
ALDOMetaboliteCHEBI:27584 (ChEBI)
CDL MetaboliteCHEBI:17933 (ChEBI)
CDLMetaboliteCHEBI:17933 (ChEBI)
CGA ProteinP01215 (Uniprot-TrEMBL)
CH3CHOMetaboliteCHEBI:15343 (ChEBI)
CHOL MetaboliteCHEBI:16113 (ChEBI)
CORMetaboliteCHEBI:16962 (ChEBI)
CORSTMetaboliteCHEBI:16827 (ChEBI)
CORTMetaboliteCHEBI:17650 (ChEBI)
CTAMetaboliteCHEBI:47828 (ChEBI)
CTLMetaboliteCHEBI:17823 (ChEBI)
CUBN

DBP

calcidiol		ComplexREACT_14197 (Reactome)
CUBN ProteinO60494 (Uniprot-TrEMBL)
CUBNProteinO60494 (Uniprot-TrEMBL)
CYP11A1ProteinP05108 (Uniprot-TrEMBL)
CYP11B1ProteinP15538 (Uniprot-TrEMBL)
CYP11B2ProteinP19099 (Uniprot-TrEMBL)
CYP17A1ProteinP05093 (Uniprot-TrEMBL)
CYP19A1ProteinP11511 (Uniprot-TrEMBL)
CYP21A2ProteinP08686 (Uniprot-TrEMBL)
CYP24A1ProteinQ07973 (Uniprot-TrEMBL)
CYP27B1ProteinO15528 (Uniprot-TrEMBL) The start coordinate is not yet known
CYP2R1ProteinQ6VVX0 (Uniprot-TrEMBL)
Cubilin

DBP

Calcidiol		ComplexREACT_14090 (Reactome)
Cubilin

DBP

Calcidiol		ComplexREACT_14699 (Reactome)
DBP CalcidiolComplexREACT_14039 (Reactome)
DBP vitamin D3ComplexREACT_14420 (Reactome)
DHEAMetaboliteCHEBI:28689 (ChEBI)
DHTESTMetaboliteCHEBI:16330 (ChEBI)
DOCMetaboliteCHEBI:16973 (ChEBI)
E1MetaboliteCHEBI:17263 (ChEBI)
EST17bMetaboliteCHEBI:16469 (ChEBI)
GC ProteinP02774 (Uniprot-TrEMBL)
GCProteinP02774 (Uniprot-TrEMBL)
H+MetaboliteCHEBI:15378 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HCOOHMetaboliteCHEBI:30751 (ChEBI)
HSD11B1 ProteinP28845 (Uniprot-TrEMBL)
HSD11B1 dimerComplexREACT_10331 (Reactome)
HSD17B1 ProteinP14061 (Uniprot-TrEMBL)
HSD17B1 dimerComplexREACT_27045 (Reactome)
HSD17B3ProteinP37058 (Uniprot-TrEMBL)
HSD2B1 or HSD3B2 dimerComplexREACT_10470 (Reactome)
ISCALMetaboliteCHEBI:17998 (ChEBI)
LGMNProteinQ99538 (Uniprot-TrEMBL)
LHB ProteinP01229 (Uniprot-TrEMBL)
LRP2ProteinP98164 (Uniprot-TrEMBL)
LutropinComplexREACT_17811 (Reactome)
MePeOHMetaboliteCHEBI:63910 (ChEBI)
NAD+MetaboliteCHEBI:15846 (ChEBI)
NADHMetaboliteCHEBI:16908 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
P4MetaboliteCHEBI:17026 (ChEBI)
POMCProteinP01189 (Uniprot-TrEMBL)
PREGMetaboliteCHEBI:16581 (ChEBI)
PregnenoloneMetaboliteCHEBI:16581 (ChEBI)
SRD5A1 or 2 or 3ProteinREACT_23017 (Reactome)
STAR ProteinP49675 (Uniprot-TrEMBL)
STARProteinP49675 (Uniprot-TrEMBL)
StAR-related cholesterol-binding proteinsProteinREACT_10617 (Reactome)
TESMetaboliteCHEBI:17347 (ChEBI)
VD3 MetaboliteCHEBI:28940 (ChEBI)
VD3MetaboliteCHEBI:28940 (ChEBI)
cholesterol STARComplexREACT_10256 (Reactome)
cholesterol StAR-related proteinComplexREACT_10388 (Reactome)
cholesterol MetaboliteCHEBI:16113 (ChEBI)
cholesterolMetaboliteCHEBI:16113 (ChEBI)
pregn-5-ene-3,20-dione-17-olMetaboliteCHEBI:63843 (ChEBI)
pregn-5-ene-3,20-dioneMetaboliteCHEBI:63837 (ChEBI)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
11-deoxycortisolArrowREACT_9996 (Reactome)
11-deoxycortisolREACT_10037 (Reactome)
17alpha-hydroxypregnenoloneArrowREACT_9993 (Reactome)
17alpha-hydroxypregnenoloneREACT_10026 (Reactome)
17alpha-hydroxypregnenoloneREACT_10031 (Reactome)
17alpha-hydroxyprogesteroneArrowREACT_10116 (Reactome)
17alpha-hydroxyprogesteroneREACT_10013 (Reactome)
17alpha-hydroxyprogesteroneREACT_9996 (Reactome)
18-hydroxycorticosteroneArrowREACT_10045 (Reactome)
18-hydroxycorticosteroneREACT_10094 (Reactome)
20alpha,22beta dihydroxycholesterolArrowREACT_10084 (Reactome)
20alpha,22beta dihydroxycholesterolREACT_10035 (Reactome)
22beta-hydroxycholesterolArrowREACT_9956 (Reactome)
22beta-hydroxycholesterolREACT_10084 (Reactome)
4-Androstene-3, 17-dioneArrowREACT_10013 (Reactome)
4-Androstene-3, 17-dioneArrowREACT_10056 (Reactome)
4-Androstene-3, 17-dioneREACT_9948 (Reactome)
4-Androstene-3, 17-dioneREACT_9954 (Reactome)
AKR1B1mim-catalysisREACT_9986 (Reactome)
ALDOArrowREACT_10094 (Reactome)
CDLArrowREACT_13458 (Reactome)
CDLArrowREACT_13664 (Reactome)
CDLREACT_13461 (Reactome)
CDLREACT_13628 (Reactome)
CH3CHOArrowREACT_10013 (Reactome)
CH3CHOArrowREACT_10026 (Reactome)
CORArrowREACT_10043 (Reactome)
CORSTArrowREACT_10117 (Reactome)
CORSTREACT_10045 (Reactome)
CORTArrowREACT_10037 (Reactome)
CORTREACT_10043 (Reactome)
CTAArrowREACT_13667 (Reactome)
CTLArrowREACT_13628 (Reactome)
CTLREACT_13667 (Reactome)
CUBNArrowREACT_13664 (Reactome)
CUBNREACT_13631 (Reactome)
CYP11A1mim-catalysisREACT_10035 (Reactome)
CYP11A1mim-catalysisREACT_10084 (Reactome)
CYP11A1mim-catalysisREACT_9956 (Reactome)
CYP11B1mim-catalysisREACT_10037 (Reactome)
CYP11B1mim-catalysisREACT_10117 (Reactome)
CYP11B2mim-catalysisREACT_10045 (Reactome)
CYP11B2mim-catalysisREACT_10094 (Reactome)
CYP17A1mim-catalysisREACT_10013 (Reactome)
CYP17A1mim-catalysisREACT_10026 (Reactome)
CYP17A1mim-catalysisREACT_10116 (Reactome)
CYP17A1mim-catalysisREACT_9993 (Reactome)
CYP19A1mim-catalysisREACT_9954 (Reactome)
CYP19A1mim-catalysisREACT_9963 (Reactome)
CYP21A2mim-catalysisREACT_10032 (Reactome)
CYP21A2mim-catalysisREACT_9996 (Reactome)
CYP24A1mim-catalysisREACT_13667 (Reactome)
CYP27B1mim-catalysisREACT_13628 (Reactome)
CYP2R1mim-catalysisREACT_13458 (Reactome)
DBP CalcidiolREACT_13631 (Reactome)
DHEAArrowREACT_10026 (Reactome)
DHEAREACT_10056 (Reactome)
DHTESTArrowREACT_22210 (Reactome)
DOCArrowREACT_10032 (Reactome)
DOCREACT_10117 (Reactome)
E1ArrowREACT_9954 (Reactome)
E1REACT_25243 (Reactome)
EST17bArrowREACT_25243 (Reactome)
EST17bArrowREACT_9963 (Reactome)
GCArrowREACT_13727 (Reactome)
GCREACT_13461 (Reactome)
GCREACT_13585 (Reactome)
H+ArrowREACT_10031 (Reactome)
H+ArrowREACT_10043 (Reactome)
H+ArrowREACT_10056 (Reactome)
H+ArrowREACT_9989 (Reactome)
H+REACT_10013 (Reactome)
H+REACT_10026 (Reactome)
H+REACT_10032 (Reactome)
H+REACT_10035 (Reactome)
H+REACT_10037 (Reactome)
H+REACT_10045 (Reactome)
H+REACT_10084 (Reactome)
H+REACT_10094 (Reactome)
H+REACT_10116 (Reactome)
H+REACT_10117 (Reactome)
H+REACT_13458 (Reactome)
H+REACT_13628 (Reactome)
H+REACT_13667 (Reactome)
H+REACT_22210 (Reactome)
H+REACT_25243 (Reactome)
H+REACT_9948 (Reactome)
H+REACT_9954 (Reactome)
H+REACT_9956 (Reactome)
H+REACT_9963 (Reactome)
H+REACT_9986 (Reactome)
H+REACT_9993 (Reactome)
H+REACT_9996 (Reactome)
H2OArrowREACT_10013 (Reactome)
H2OArrowREACT_10026 (Reactome)
H2OArrowREACT_10032 (Reactome)
H2OArrowREACT_10035 (Reactome)
H2OArrowREACT_10037 (Reactome)
H2OArrowREACT_10045 (Reactome)
H2OArrowREACT_10084 (Reactome)
H2OArrowREACT_10094 (Reactome)
H2OArrowREACT_10116 (Reactome)
H2OArrowREACT_10117 (Reactome)
H2OArrowREACT_13458 (Reactome)
H2OArrowREACT_13628 (Reactome)
H2OArrowREACT_13667 (Reactome)
H2OArrowREACT_9954 (Reactome)
H2OArrowREACT_9956 (Reactome)
H2OArrowREACT_9963 (Reactome)
H2OArrowREACT_9993 (Reactome)
H2OArrowREACT_9996 (Reactome)
HCOOHArrowREACT_9954 (Reactome)
HCOOHArrowREACT_9963 (Reactome)
HSD11B1 dimermim-catalysisREACT_10043 (Reactome)
HSD17B1 dimermim-catalysisREACT_25243 (Reactome)
HSD17B3mim-catalysisREACT_9948 (Reactome)
HSD2B1 or HSD3B2 dimermim-catalysisREACT_10021 (Reactome)
HSD2B1 or HSD3B2 dimermim-catalysisREACT_10031 (Reactome)
HSD2B1 or HSD3B2 dimermim-catalysisREACT_10056 (Reactome)
HSD2B1 or HSD3B2 dimermim-catalysisREACT_9981 (Reactome)
HSD2B1 or HSD3B2 dimermim-catalysisREACT_9989 (Reactome)
ISCALArrowREACT_10035 (Reactome)
ISCALREACT_9986 (Reactome)
LGMNmim-catalysisREACT_13664 (Reactome)
LRP2mim-catalysisREACT_13608 (Reactome)
LutropinArrowREACT_10021 (Reactome)
LutropinArrowREACT_9948 (Reactome)
MePeOHArrowREACT_9986 (Reactome)
NAD+REACT_10031 (Reactome)
NAD+REACT_10056 (Reactome)
NAD+REACT_9989 (Reactome)
NADHArrowREACT_10031 (Reactome)
NADHArrowREACT_10056 (Reactome)
NADHArrowREACT_9989 (Reactome)
NADP+ArrowREACT_10013 (Reactome)
NADP+ArrowREACT_10026 (Reactome)
NADP+ArrowREACT_10032 (Reactome)
NADP+ArrowREACT_10035 (Reactome)
NADP+ArrowREACT_10037 (Reactome)
NADP+ArrowREACT_10045 (Reactome)
NADP+ArrowREACT_10084 (Reactome)
NADP+ArrowREACT_10094 (Reactome)
NADP+ArrowREACT_10116 (Reactome)
NADP+ArrowREACT_10117 (Reactome)
NADP+ArrowREACT_13458 (Reactome)
NADP+ArrowREACT_13628 (Reactome)
NADP+ArrowREACT_13667 (Reactome)
NADP+ArrowREACT_22210 (Reactome)
NADP+ArrowREACT_25243 (Reactome)
NADP+ArrowREACT_9948 (Reactome)
NADP+ArrowREACT_9954 (Reactome)
NADP+ArrowREACT_9956 (Reactome)
NADP+ArrowREACT_9963 (Reactome)
NADP+ArrowREACT_9986 (Reactome)
NADP+ArrowREACT_9993 (Reactome)
NADP+ArrowREACT_9996 (Reactome)
NADP+REACT_10043 (Reactome)
NADPHArrowREACT_10043 (Reactome)
NADPHREACT_10013 (Reactome)
NADPHREACT_10026 (Reactome)
NADPHREACT_10032 (Reactome)
NADPHREACT_10035 (Reactome)
NADPHREACT_10037 (Reactome)
NADPHREACT_10045 (Reactome)
NADPHREACT_10084 (Reactome)
NADPHREACT_10094 (Reactome)
NADPHREACT_10116 (Reactome)
NADPHREACT_10117 (Reactome)
NADPHREACT_13458 (Reactome)
NADPHREACT_13628 (Reactome)
NADPHREACT_13667 (Reactome)
NADPHREACT_22210 (Reactome)
NADPHREACT_25243 (Reactome)
NADPHREACT_9948 (Reactome)
NADPHREACT_9954 (Reactome)
NADPHREACT_9956 (Reactome)
NADPHREACT_9963 (Reactome)
NADPHREACT_9986 (Reactome)
NADPHREACT_9993 (Reactome)
NADPHREACT_9996 (Reactome)
O2REACT_10013 (Reactome)
O2REACT_10026 (Reactome)
O2REACT_10032 (Reactome)
O2REACT_10035 (Reactome)
O2REACT_10037 (Reactome)
O2REACT_10045 (Reactome)
O2REACT_10084 (Reactome)
O2REACT_10094 (Reactome)
O2REACT_10116 (Reactome)
O2REACT_10117 (Reactome)
O2REACT_13458 (Reactome)
O2REACT_13628 (Reactome)
O2REACT_13667 (Reactome)
O2REACT_9954 (Reactome)
O2REACT_9956 (Reactome)
O2REACT_9963 (Reactome)
O2REACT_9993 (Reactome)
O2REACT_9996 (Reactome)
P4REACT_10032 (Reactome)
P4REACT_10116 (Reactome)
POMCArrowREACT_10026 (Reactome)
POMCArrowREACT_10037 (Reactome)
POMCArrowREACT_10056 (Reactome)
POMCArrowREACT_22210 (Reactome)
POMCArrowREACT_9948 (Reactome)
PREGREACT_9989 (Reactome)
PREGREACT_9993 (Reactome)
PregnenoloneArrowREACT_10035 (Reactome)
REACT_10013 (Reactome) 17Alpha-hydroxyprogesterone, NADPH + H+, and O2 react to form 4-Androstene-3, 17-dione, NADP+, H2O, and acetaldehyde. CYP17 (which also catalyzes 17-alpha-hydroxylation) catalyzes this lyase reaction. There are marked species differences in which substrate is used for this lyase activity.
REACT_10021 (Reactome) Pregn-5-ene-3,20-dione isomerizes to progesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
The hormone lutropin (LH) triggers ovulation and development of the corpus luteum, that in turn increases production of progesterone.
REACT_10023 (Reactome) Cortisol is translocated from the mitochondrial matrix into the cytosol by an unknown mechanism.
REACT_10026 (Reactome) 17-alpha-hydroxypregnenolone, NADPH + H+, and O2 react to form DHA (dehydroepiandrostenedione), NADP+, H2O, and acetaldehyde. CYP17 (which also catalyzes 17-alpha-hydroxylation) catalyzes this lyase reaction. There are marked species differences in which substrate is used for this lyase activity. The human enzyme prefers 17alpha-pregnenolone (delta5 steroid) as substrate (Brock, BJ, Waterman, MR, 1999). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
REACT_10031 (Reactome) 17-Hydroxypregnenolone and NAD+ react to form pregn-5-ene-3,20-dione-17-ol and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
REACT_10032 (Reactome) Progesterone, NAPDH + H+, and O2 react to form 11-deoxycorticosterone, NADP+ and H2O. This reaction is catalyzed by CYP21A2 associated with the endoplasmic reticulum membrane.
REACT_10035 (Reactome) 20alpha,22beta-hydroxycholesterol, NADPH + H+, and O2 react to form pregnenolone, isocaproaldehyde, NADP+ and H2O. This cleavage reaction is catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane. Pregnenolone is substantially more hydrophilic than cholesterol and hydroxycholesterol and is released into the mitochondrial matrix.
REACT_10037 (Reactome) 11-Deoxycortisol, NADPH + H+, and O2 react to form cortisol, NADP+, and H2O. This reaction is catalyzed by CYP11B1 associated with the inner mitochondrial membrane. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
REACT_10043 (Reactome) Cortisol and NADP+ react to form cortisone, NADPH, and H+. This reaction is catalyzed by 11beta-hydroxysteroid dehydrogenase (11beta-HSD), associated with the endoplasmic reticulum membrane. The conversion of cortisol, an active hormone, into inactive cortisone occurs in many tissues in the body, notably in the liver, and appears to play a role in regulating cortison activity.
REACT_10045 (Reactome) Corticosterone, NADPH + H+, and O2 react to form 18-hydroxycorticosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
REACT_10056 (Reactome) In this two-step reaction catalyzed by 3beta-HSD associated with the endoplasmic reticulum membrane, the 3-hydroxyl group of DHA is oxidized to a keto group and the double bond in the steroid nucleus is then isomerized from the five to the 4 position. Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
REACT_10063 (Reactome) Pregenolone is translocated from the mitochondrial matrix to the cytosol. Neither transport proteins to mediate its movement across the inner mitochondrial membrane nor carrier proteins to facilitate its movement in the cytosol have been identified, and the mechanism of this translocation is unknown.
REACT_10076 (Reactome) Cholesterol is released from its complex with STAR in the mitochondrial intermembrane space. The mechanism of this process in vivo remains incompletely understood.
REACT_10084 (Reactome) 22beta-hydroxycholesterol, NADPH + H+, and O2 react to form 20alpha,22beta-hydroxycholesterol, NADP+ and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane.
REACT_10093 (Reactome) 11-deoxycortisol is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized to cortisol in a reaction catalyzed by mitochondrial enzymes. The means by which 11-deoxycortisol translocates into the mitochondrial matrix, however, is unknown.
REACT_10094 (Reactome) 18-Hydroxycorticosterone and NADPH + H+ react to form aldosterone, NADP+, and H2O. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
REACT_10116 (Reactome) Progesterone, NADPH + H+, and O2 react to form 17alpha-hydroxyprogesterone, NADP+, and H2O, catalyzed by CYP17 (steroid 17alpha-monooxygenase), associated with the endoplasmic reticulum membrane.
REACT_10117 (Reactome) 11-Deoxycorticosterone, NADPH + H+, and O2 react to form corticosterone, H2O, and NADP+. This reaction is catalyzed by CYP11B2 associated with the inner mitochondrial membrane.
REACT_13458 (Reactome) To be functionally active, vitamin D is required to be dihydroxylated. The first hydroxylation at position 25 is carried out by vitamin D 25-hydroxylase (CYP2R1) in the liver, forming calcidiol.
REACT_13461 (Reactome) Vitamin D binding protein (DBP), a plasma protein, carries the vitamin D metabolites in the circulation. Calcidiol translocates to the extracellular region where it binds with DBP and is transported to the kidney.
REACT_13530 (Reactome) The internalized complex enters the lysosome where it can be acted upon the protease legumain.
REACT_13585 (Reactome) Vitamin D metabolites are lipophilic and must be transported in the circulation bound to plasma proteins. Vitamin D3 is transported to the liver bound to a plasma protein called vitamin D binding protein (DBP).
REACT_13608 (Reactome) Megalin (glycoprotein 330) is a member of the low density lipoprotein receptor family and is abundant in kidney proximal tubules. Megalin mediates the endocytic uptake of DBP:Calcidiol complexes to prevent loss of calcidiol in urine.
REACT_13628 (Reactome) The second step in vitamin D3 activation requires further hydroxylation of 25-hydroxyvitamin D3 (calcidiol) to 1alpha-25-dihydroxyvitamin D3 (calcitriol). This conversion is mediated by 25-hydroxyvitamin D-1alpha hydroxylase (CYP27B1).
REACT_13631 (Reactome) Cubilin is a membrane-associated protein colocalizing with megalin. Its function is to sequester steroid carrier complexes on the cell surface before megalin mediates their internalization.
REACT_13664 (Reactome) Mammalian legumain (asparagine-specific endoprotease) is a subfamily of cysteine proteases with no homology to other known proteases and is found in a wide range of organisms from parasites to plants and animals. Legumain requires acidic conditions for its degradative activity and has strict specificity for cleavage with an asparagine residue in the P1 site. Cubilin, once released from the complex, cycles back to the cell surface. Calcidiol also becomes available for further processing.
REACT_13666 (Reactome) The skin's exposure to UV rays from sunlight induces the photolytic cleavage of 7-dehydrocholesterol to previtamin D3. This is followed by thermal isomerization to form vitamin D3 (Cholecalciferol).
REACT_13667 (Reactome) Calcitriol (1,25(OH)2-D3) is biologically inactivated through a series of reactions beginning with 24-hydroxylation and is most likely a mechanism of elimination. 24-Hydroxylation of the vitamin D metabolites is largely regulated inversely to 1-hydroxylation, the initial step towards activation.
REACT_13727 (Reactome) Once vitamin D3 is released from DBP, it becomes available for hydroxylation.
REACT_13792 (Reactome) Once out of the lysosome, calcidiol binds to intracellular vitamin D binding protein (IDBP) which facilitates the localization of vitamin D metabolites in the cell. IDBPs are related to the hsc-70 family of heat shock proteins and demonstrate a high nucleotide homology to that family. No IDBP protein has been documented yet so IDBP has not been annotated.
REACT_22210 (Reactome) The conversion of testosterone to the most potent androgen, 5-alpha-dihydrotestosterone (DHT), is catalyzed by the microsomal 5alpha-steroid reductase enzymes, of which there are three reported types in humans to date (SRD5A1-3) (Andersson S and Russell DW, 1990; Andersson S et al, 1991; Uemura M et al, 2008 respectively). These enzymes are expressed in the prostate and other androgen target sites. Defects in SRD5A2 are the cause of pseudovaginal perineoscrotal hypospadias, also known as male pseudohermaphroditism (Anwar R et al, 1997). Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
REACT_25243 (Reactome) Expression of HSD17B1 which is the main enzyme that catalyzes the hydrogenation of estrone is strongly restricted to placenta, ovaries, endometrium and breast tissue (Moeller and Adamski, 2009).
REACT_9948 (Reactome) The 17HSD family of enzymes catalyze the final step in the synthesis of estradiol and testosterone. They convert inactive 17-ketosteroids to their active 17beta-hydroxy forms. Androstenedione, a ketosteroid, is reduced to testosterone, a highly potent androgen, by the enzyme 17beta-hydroxysteroid dehydrogenase isoform III (17HSD3). The other human isoforms of 17HSDs to take part in the final steps of active steroid biosynthesis are types 1 and VII, which reduce estrone to estradiol.
Corticotropin (Adrenocorticotropic hormone, ACTH) acts through the ACTH receptor called melanocortin receptor type 2 (MC2R) to stimulate steroidogenesis, increasing the production of androgens (McKenna et al, 1997).
In males, Lutropin (LH) stimulates testosterone production.
REACT_9954 (Reactome) The conversion of androstenedione to estrone is catalyzed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane.
REACT_9956 (Reactome) Cholesterol and NADPH + H+ react to form 22beta-hydroxycholesterol, NADP+, and H2O, catalyzed by CYP11A (P450scc) associated with the inner mitochondrial membrane.
REACT_9961 (Reactome) Isocaproaldehyde (4-methylpentanal) is translocated from the mitochondrial matrix to the cytosol. The transporter that mediates this reaction is unknown. The reaction is inferred to exist because isocaproaldehyde is generated within the mitochondrion while the enzyme that reduces it to the corresponding alcohol is located in the cytosol (Matsuura et al. 1996).
REACT_9963 (Reactome) The conversion of testosterone to estradiol is catalyzed by aromatase (CYP19A1) associated with the endoplasmic reticulum membrane.
REACT_9966 (Reactome) 11-deoxycorticosterone is synthesized in a reaction at the endoplasmic reticulum membrane and is further metabolized, ultimately to yield aldosterone, in reactions catalyzed by mitochondrial enzymes. The means by which 11-deoxycorticosterone translocates into the mitochondrial matrix, however, is unknown.
REACT_9973 (Reactome) Cholesterol traverses the cytosol and the mitochondrial intermembrane space complexed with carrier proteins. This process is essential for the synthesis of steroid hormones in humans. Nevertheless, molecular details of the transport process remain incompletely understood. A plausible model, supported by studies in vitro and in cells overexpressing cloned human proteins, is that cytosolic STAR-related proteins STARD4, 5, and 6 bind cholesterol liberated from lysosomes or cytosolic lipid droplets and carry it to the outer mitochondrial membrane (Rodriguez-Aguado et al. 2005; Soccio et al. 2002), where it is transferred to STAR protein and carried across the mitochondrial intermembrane space (Miller 2007).

Mutations in the gene encoding STAR block synthesis of all steroid hormones in humans, indicating the critical importance of this transport step in the biosynthetic process (Bose et al. 1996). The transport step is also a key site for normal regulation of steroid hormone synthesis, as STAR protein is unstable and its synthesis is up-regulated in response to signals such as the binding of ACTH to its receptors on adrenal cells (Stocco 2001).

REACT_9981 (Reactome) Pregn-5-ene-3,20-dione-17-ol isomerizes to 17-hydroxyprogesterone. This reaction is catalyzed by the isomerase activity of 3 beta-HSD, associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
REACT_9986 (Reactome) Isocaproaldehyde is reduced by NADPH + H+ to yield 4-methylpentan-1-ol and NADP+. This cytosolic reaction is catalyzed by AKR1B1 (aldose reductase). The purified human enzyme has been shown to catalyze this reaction efficiently in vitro; its abundance in adrenal tissue in humans and other mammals and its concordant expression with other enzymes of steroid hormone synthesis are consistent with it performing this role in vivo as well (Matsuura et al. 1996; Lefrancois-Martinez et al. 2004). The metabolic fate of 4-methylpentan-1-ol is unknown.
REACT_9989 (Reactome) Pregnenolone and NAD+ react to form pregn-5-ene-3,20-dione and NADH + H+. This reaction is catalyzed by the 3 beta-hydroxysteroid activity of 3-beta-hydroxysteroid dehydrogenase/isomerase (HSD3B) enzyme associated with the endoplasmic reticulum membrane. The active form of the enzyme is a homodimer. The enzyme occurs in two isoforms that are similar in their biochemical properties but differ in their tissue expression: type I (HSD3B1) is found in placenta and skin, while type II (HSD3B2) is found in the adrenal glands and gonads.
REACT_9993 (Reactome) Pregnenolone and NADPH + H+ react to form 17alpha-hydroxypregnenolone, NADP+, and H2O. CYP17A1 (steroid 17alpha-monooxygenase) associated with the endoplasmic reticulum membrane catalyzes this reaction.
REACT_9996 (Reactome) 17-Hydroxyprogesterone, NADPH + H+, and O2 react to form 11-deoxycortisol, NADP+, and H2O. This reaction is catalyzed by CYP21A2 (steroid 21-hydroxylase) associated with the endoplasmic reticulum membrane.
SRD5A1 or 2 or 3mim-catalysisREACT_22210 (Reactome)
STARArrowREACT_10076 (Reactome)
STARREACT_9973 (Reactome)
StAR-related cholesterol-binding proteinsArrowREACT_9973 (Reactome)
TESArrowREACT_9948 (Reactome)
TESREACT_22210 (Reactome)
TESREACT_9963 (Reactome)
VD3ArrowREACT_13727 (Reactome)
VD3REACT_13458 (Reactome)
VD3REACT_13585 (Reactome)
cholesterol STARArrowREACT_9973 (Reactome)
cholesterol StAR-related proteinREACT_9973 (Reactome)
cholesterolArrowREACT_10076 (Reactome)
cholesterolREACT_9956 (Reactome)
pregn-5-ene-3,20-dione-17-olArrowREACT_10031 (Reactome)
pregn-5-ene-3,20-dioneArrowREACT_9989 (Reactome)

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