TESTOSTERONE BIOSYNTHETIC PATHWAY (PW:0000778)
Description
Androgen hormones are responsible for the development and maintenance of male phenotype and reproductive functions and a range of other processes in nonreproductive tissues. Testosterone, the main androgen, is primarily synthesized in the testes; others are synthesized in the adrenal gland and can be converted to testosterone in peripheral tissues. Like all steroid hormones, androgens are derived from cholesterol; their biosynthesis is tightly regulated by the hypothalamus-pituitary-gonadal axis. The chronic steroidogenic response involves the change in the expression of steroidogenic genes while the acute response involves the quick delivery of cholesterol to the site of the first enzymatic reaction. The rapid flux of cholesterol from the outer (OMM) to the inner (IMM) mitochondrial membrane is mediated by the StAR protein. The IMM is the site where Cyp11a1, the enzyme catalyzing the first and rate-limiting step in the steroid biosynthetic pathway, is located. Overall there are two major classes of enzymes: the heme-containing cytochrome P450 and the hydroxysteroid dehydrogenase enzymes. The members of P450 superfamily that participate in the pathway are membrane-bound mitochondrial or endoplasmic reticulum (microsome) enzymes that utilize NADPH as an electron donor. Two proteins mediate the mitochondrial electron transfer - the flavin containing Fdxr and the iron-sulfur Fdx1; only one protein mediates the microsomal electron transfer - the P450 (cytochrome) oxidoreductase Por with two flavin cofactors. Dehydrogenases are membrane-bound mitochondrial or microsomal enzymes that utilize NAD or NADPH depending on whether the reaction is oxidation or reduction. The 27-carbon cholesterol is converted to the C
21 pregnenolone in a series of three chemical reactions that together constitute the step catalyzed by Cyp11a1. Cyp17a1 catalyzes the conversion of pregnenolone to 17OH-pregnenolone; in a second step, 17OH-pregnenolone is cleaved at the C
17 -C
20 bond by the lyase activity of the enzyme to produce the C
19 androgen dehydroepiandrosterone (DHEA). Cyp17a1 can also convert the pregnenolone derived progesterone to 17OH-progesterone which is then cleaved to C
19 androstenedione. This route (not shown) is insignificant in humans but it is used by other species. DHEA can be sulfonated to DHEAS by Sult2a; the reverse reaction is caried out by steroid sulfatase Sts. DHEAS:DHEA ratio links to physiological as well as pathophysiological states. DHEA is converted to androstenediol or to androstenedione by hydroxysteroid dehydrogenase Hsd17b3, and Hsd3b1 or Hsd3b2, respectively. Androstenediol and androstenedione are then converted to testosterone by the action of Hsd3b1 or Hsd3b2, and Hsd17b3, respectively. Testosterone can be oxidized and thus inactivated to its androstenedione precursor by the action of Hsd17b2. In some of the target tissues, testosterone can be converted into its very potent metabolite dihydrotestosterone (DHT) by steroid-5-alpha reductases. DHT has a greater affinity for the androgen receptor and thus is a more powerful initiator of the androgen signaling pathway.
To see the ontology report for annotations, GViewer and download, click here
The testosterone biosynthetic pathway is part of the Steroid Hormone Biosynthesis Pathway Suite and the Prostate Cancer Pathway Suite . Click the name of the suite to view the related pathways....(less)
Pathway Diagram:
Genes in Pathway:
G
Cyp11a1
cytochrome P450, family 11, subfamily a, polypeptide 1
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 8:58,422,807...58,434,342
Ensembl chr 8:58,404,669...58,434,338
G
Cyp17a1
cytochrome P450, family 17, subfamily a, polypeptide 1
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 1:245,535,462...245,543,148
Ensembl chr 1:245,535,462...245,541,573
G
Fdx1
ferredoxin 1
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 8:52,268,536...52,287,344
Ensembl chr 8:52,268,536...52,287,414
G
Fdxr
ferredoxin reductase
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr10:100,507,863...100,516,649
Ensembl chr10:100,507,865...100,516,658
G
Hsd17b2
hydroxysteroid (17-beta) dehydrogenase 2
ISO
RGD
PMID:15583024
RGD:4889549
NCBI chr19:45,753,576...45,825,203
Ensembl chr19:45,753,574...45,825,202
G
Hsd17b3
hydroxysteroid (17-beta) dehydrogenase 3
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr17:1,027,229...1,058,554
Ensembl chr17:1,027,229...1,058,554
G
Hsd3b1
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1
ISO
RGD
PMID:15583024
RGD:4889549
NCBI chr 2:186,169,864...186,175,984
Ensembl chr 2:186,169,863...186,175,999
G
Hsd3b2
hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 2
ISO
RGD
PMID:15583024
RGD:4889549
NCBI chr 2:186,095,897...186,105,354
Ensembl chr 2:186,095,897...186,101,852
G
Por
cytochrome p450 oxidoreductase
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr12:20,951,058...20,999,198
Ensembl chr12:20,951,058...20,999,245
G
Srd5a1
steroid 5 alpha-reductase 1
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 1:33,686,069...33,720,468
Ensembl chr 1:33,686,391...33,720,461
G
Srd5a2
steroid 5 alpha-reductase 2
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 6:21,426,225...21,465,727
Ensembl chr 6:21,426,215...21,462,112
G
Star
steroidogenic acute regulatory protein
TAS
RGD
PMID:18821018
RGD:2325883
NCBI chr16:66,267,094...66,274,368
Ensembl chr16:66,264,807...66,271,672
G
Sts
steroid sulfatase
ISO
RGD
PMID:21693170
RGD:6893583
NCBI chr X:42,225,131...42,233,403
Ensembl chr X:42,225,372...42,233,402
G
Sult2a1
sulfotransferase family 2A member 1
ISO
RGD
PMID:18821018
RGD:2325883
NCBI chr 1:75,451,178...75,508,113
Ensembl chr 1:74,911,100...75,508,134
Pathway Gene Annotations
Disease Annotations Associated with Genes in the testosterone biosynthetic pathway
Cyp11a1 46, XY Disorders of Sex Development , Adrenal Insufficiency , autism spectrum disorder , Bardet-Biedl syndrome , Bloom syndrome , Brain Injuries , Cardiomegaly , chronic obstructive pulmonary disease , colorectal cancer , congenital adrenal hyperplasia , congenital adrenal insufficiency , Endometrial Neoplasms , Experimental Diabetes Mellitus , Fetal Growth Retardation , genetic disease , hyperglycemia , hypertension , hypogonadism , Lipoid Congenital Adrenal Hyperplasia , nephrosis , schizophrenia , sciatic neuropathy , status epilepticus , type 2 diabetes mellitus Cyp17a1 17,20-Lyase Deficiency, Isolated , amenorrhea , breast cancer , Breast Neoplasms , cholelithiasis , congenital adrenal hyperplasia , Congenital Adrenal Hyperplasia due to 21 Hydroxylase Deficiency , Congenital Adrenal Hyperplasia, Type 5 , Experimental Liver Cirrhosis , Female Infertility , gallbladder cancer , genetic disease , Genetic Predisposition to Disease , hepatocellular carcinoma , Hyperkalemia , hypogonadism , hypopituitarism , male infertility , malignant hypertension , metabolic dysfunction-associated steatotic liver disease , Neuralgia , nevoid basal cell carcinoma syndrome , Oligomenorrhea , osteoporosis , ovarian cyst , pancreatic cancer , polycystic ovary syndrome , primary ovarian insufficiency , prostate cancer , Prostatic Neoplasms , sciatic neuropathy , sexual health disorder , urinary bladder cancer Fdx1 ataxia telangiectasia , Chromosome 11, Partial Trisomy 11q , genetic disease , intellectual disability , pancreatitis Fdxr Arterial Occlusive Diseases , Auditory Neuropathy , Auditory Neuropathy and Optic Atrophy , genetic disease , OPTIC ATROPHY-ATAXIA-PERIPHERAL NEUROPATHY-GLOBAL DEVELOPMENTAL DELAY SYNDROME Hsd17b2 Endometrial Neoplasms , endometriosis , Experimental Liver Cirrhosis , genetic disease Hsd17b3 17-beta hydroxysteroid dehydrogenase 3 deficiency , Alzheimer's disease , disorder of sexual development , genetic disease , intellectual disability , Prostatic Neoplasms , pseudohermaphroditism , type 2 diabetes mellitus Hsd3b1 Alzheimer's disease , autism spectrum disorder , genetic disease , Hajdu-Cheney syndrome , hyperprolactinemia , hypertension , hypogonadism , hypospadias , hypothyroidism , PHGDH deficiency , polycystic ovary syndrome , Prostatic Neoplasms , sciatic neuropathy , type 2 diabetes mellitus Hsd3b2 Adrenal Hyperplasia 2 , Alzheimer's disease , congenital adrenal hyperplasia , cryptorchidism , genetic disease , Hajdu-Cheney syndrome , hepatocellular carcinoma , high grade glioma , hyperprolactinemia , hypertension , hypospadias , Hypospadias 1, X-Linked , Paranoid Disorders , PHGDH deficiency , polycystic ovary syndrome , Prostatic Neoplasms Por 46, XY Disorders of Sex Development , amenorrhea , Antley-Bixler syndrome , Antley-Bixler syndrome with disordered steroidogenesis , Antley-Bixler syndrome without disordered steroidogenesis , Chromosome 7q11.23 Deletion Syndrome, Distal, 1.2-MB , congenital adrenal hyperplasia , Congenital Adrenal Hyperplasia due to 21 Hydroxylase Deficiency , congestive heart failure , cytochrome P450 oxidoreductase deficiency , disorder of sexual development , Fine-Lubinsky Syndrome , genetic disease , gliosarcoma , Hirschsprung's disease , Hypotension , learning disability , Lung Injury , Musculoskeletal Abnormalities , Neoplastic Cell Transformation , neural tube defect , pleomorphic xanthoastrocytoma , primary ovarian insufficiency , urinary bladder cancer Srd5a1 breast carcinoma , Cardiomegaly , COVID-19 , endometriosis , Experimental Liver Cirrhosis , genetic disease , hyperprolactinemia , hypothyroidism , obesity , polycystic ovary syndrome , prostate cancer , prostatic hypertrophy , Prostatic Neoplasms , type 2 diabetes mellitus Srd5a2 alopecia , autism spectrum disorder , Autoinflammation with Infantile Enterocolitis , breast carcinoma , diabetes mellitus , Endometrial Neoplasms , endometriosis , familial cold autoinflammatory syndrome 4 , genetic disease , hereditary spastic paraplegia 4 , hyperprolactinemia , hypogonadism , hypospadias , Penis Agenesis , prostate cancer , prostatic hypertrophy , Prostatic Neoplasms , Pseudovaginal Perineoscrotal Hypospadias , xanthinuria , xanthinuria type II Star Cardiomegaly , congenital adrenal hyperplasia , Endometrial Neoplasms , Experimental Diabetes Mellitus , Fetal Growth Retardation , Fever , genetic disease , hereditary spastic paraplegia 54 , hypogonadism , hypogonadotropic hypogonadism 2 with or without anosmia , hypothyroidism , Lipoid Congenital Adrenal Hyperplasia , nephrosis , paraplegia , polycystic ovary syndrome , type 2 diabetes mellitus Sts alcoholic hepatitis , amenorrhea , attention deficit hyperactivity disorder , autism spectrum disorder , autistic disorder , cerebral palsy , COVID-19 , cryptorchidism , dystonia , Experimental Diabetes Mellitus , genetic disease , hypertension , Inflammation , Insulin Resistance , Neurodevelopmental Disorders , obesity , rheumatoid arthritis , schizophrenia , steatotic liver disease , Weight Gain , X-linked ichthyosis Sult2a1 Experimental Liver Cirrhosis , genetic disease , Leber congenital amaurosis 7 , prostate cancer , Prostatic Neoplasms
17,20-Lyase Deficiency, Isolated Cyp17a1 17-beta hydroxysteroid dehydrogenase 3 deficiency Hsd17b3 46, XY Disorders of Sex Development Cyp11a1 , Por Adrenal Hyperplasia 2 Hsd3b2 Adrenal Insufficiency Cyp11a1 alcoholic hepatitis Sts alopecia Srd5a2 Alzheimer's disease Hsd17b3 , Hsd3b1 , Hsd3b2 amenorrhea Cyp17a1 , Por , Sts Antley-Bixler syndrome Por Antley-Bixler syndrome with disordered steroidogenesis Por Antley-Bixler syndrome without disordered steroidogenesis Por Arterial Occlusive Diseases Fdxr ataxia telangiectasia Fdx1 attention deficit hyperactivity disorder Sts Auditory Neuropathy Fdxr Auditory Neuropathy and Optic Atrophy Fdxr autism spectrum disorder Cyp11a1 , Hsd3b1 , Srd5a2 , Sts autistic disorder Sts Autoinflammation with Infantile Enterocolitis Srd5a2 Bardet-Biedl syndrome Cyp11a1 Bloom syndrome Cyp11a1 Brain Injuries Cyp11a1 breast cancer Cyp17a1 breast carcinoma Srd5a1 , Srd5a2 Breast Neoplasms Cyp17a1 Cardiomegaly Cyp11a1 , Srd5a1 , Star cerebral palsy Sts cholelithiasis Cyp17a1 Chromosome 11, Partial Trisomy 11q Fdx1 Chromosome 7q11.23 Deletion Syndrome, Distal, 1.2-MB Por chronic obstructive pulmonary disease Cyp11a1 colorectal cancer Cyp11a1 congenital adrenal hyperplasia Cyp11a1 , Cyp17a1 , Hsd3b2 , Por , Star Congenital Adrenal Hyperplasia due to 21 Hydroxylase Deficiency Cyp17a1 , Por Congenital Adrenal Hyperplasia, Type 5 Cyp17a1 congenital adrenal insufficiency Cyp11a1 congestive heart failure Por COVID-19 Srd5a1 , Sts cryptorchidism Hsd3b2 , Sts cytochrome P450 oxidoreductase deficiency Por diabetes mellitus Srd5a2 disorder of sexual development Hsd17b3 , Por dystonia Sts Endometrial Neoplasms Cyp11a1 , Hsd17b2 , Srd5a2 , Star endometriosis Hsd17b2 , Srd5a1 , Srd5a2 Experimental Diabetes Mellitus Cyp11a1 , Star , Sts Experimental Liver Cirrhosis Cyp17a1 , Hsd17b2 , Srd5a1 , Sult2a1 familial cold autoinflammatory syndrome 4 Srd5a2 Female Infertility Cyp17a1 Fetal Growth Retardation Cyp11a1 , Star Fever Star Fine-Lubinsky Syndrome Por gallbladder cancer Cyp17a1 genetic disease Cyp11a1 , Cyp17a1 , Fdx1 , Fdxr , Hsd17b2 , Hsd17b3 , Hsd3b1 , Hsd3b2 , Por , Srd5a1 , Srd5a2 , Star , Sts , Sult2a1 Genetic Predisposition to Disease Cyp17a1 gliosarcoma Por Hajdu-Cheney syndrome Hsd3b1 , Hsd3b2 hepatocellular carcinoma Cyp17a1 , Hsd3b2 hereditary spastic paraplegia 4 Srd5a2 hereditary spastic paraplegia 54 Star high grade glioma Hsd3b2 Hirschsprung's disease Por hyperglycemia Cyp11a1 Hyperkalemia Cyp17a1 hyperprolactinemia Hsd3b1 , Hsd3b2 , Srd5a1 , Srd5a2 hypertension Cyp11a1 , Hsd3b1 , Hsd3b2 , Sts hypogonadism Cyp11a1 , Cyp17a1 , Hsd3b1 , Srd5a2 , Star hypogonadotropic hypogonadism 2 with or without anosmia Star hypopituitarism Cyp17a1 hypospadias Hsd3b1 , Hsd3b2 , Srd5a2 Hypospadias 1, X-Linked Hsd3b2 Hypotension Por hypothyroidism Hsd3b1 , Srd5a1 , Star Inflammation Sts Insulin Resistance Sts intellectual disability Fdx1 , Hsd17b3 learning disability Por Leber congenital amaurosis 7 Sult2a1 Lipoid Congenital Adrenal Hyperplasia Cyp11a1 , Star Lung Injury Por male infertility Cyp17a1 malignant hypertension Cyp17a1 metabolic dysfunction-associated steatotic liver disease Cyp17a1 Musculoskeletal Abnormalities Por Neoplastic Cell Transformation Por nephrosis Cyp11a1 , Star neural tube defect Por Neuralgia Cyp17a1 Neurodevelopmental Disorders Sts nevoid basal cell carcinoma syndrome Cyp17a1 obesity Srd5a1 , Sts Oligomenorrhea Cyp17a1 OPTIC ATROPHY-ATAXIA-PERIPHERAL NEUROPATHY-GLOBAL DEVELOPMENTAL DELAY SYNDROME Fdxr osteoporosis Cyp17a1 ovarian cyst Cyp17a1 pancreatic cancer Cyp17a1 pancreatitis Fdx1 Paranoid Disorders Hsd3b2 paraplegia Star Penis Agenesis Srd5a2 PHGDH deficiency Hsd3b1 , Hsd3b2 pleomorphic xanthoastrocytoma Por polycystic ovary syndrome Cyp17a1 , Hsd3b1 , Hsd3b2 , Srd5a1 , Star primary ovarian insufficiency Cyp17a1 , Por prostate cancer Cyp17a1 , Srd5a1 , Srd5a2 , Sult2a1 prostatic hypertrophy Srd5a1 , Srd5a2 Prostatic Neoplasms Cyp17a1 , Hsd17b3 , Hsd3b1 , Hsd3b2 , Srd5a1 , Srd5a2 , Sult2a1 pseudohermaphroditism Hsd17b3 Pseudovaginal Perineoscrotal Hypospadias Srd5a2 rheumatoid arthritis Sts schizophrenia Cyp11a1 , Sts sciatic neuropathy Cyp11a1 , Cyp17a1 , Hsd3b1 sexual health disorder Cyp17a1 status epilepticus Cyp11a1 steatotic liver disease Sts type 2 diabetes mellitus Cyp11a1 , Hsd17b3 , Hsd3b1 , Srd5a1 , Star urinary bladder cancer Cyp17a1 , Por Weight Gain Sts X-linked ichthyosis Sts xanthinuria Srd5a2 xanthinuria type II Srd5a2