Endocrine Abstracts

In humans, androgen synthesis crucially depends on the enzyme CYP17A1 expressed in adrenals and gonads. The 17,20 lyase activity of CYP17A1 catalyses the key step in human androgen biosynthesis, the conversion of 17-hydroxypregnenolone to the universal sex steroid precursor dehydroepiandrosterone (DHEA). For its catalytic activity, CYP17A1 requires electron transfer from P450 oxidoreductase (POR). Mutations in CYP17A1 and POR are known to disrupt human androgen s...

A key component of androgen synthesis is the availability of the pro-hormone DHEA, which is either converted to active androgens or inactivated to its sulfate ester DHEAS by DHEA sulfotransferase (SULT2A1). The latter reaction requires provision of the universal sulfate donor 3′-phosphoadenosine-5′-phosphosulfate, PAPS. In humans, PAPS is generated by the PAPS synthase isoforms PAPSS1 and PAPSS2. Recently, inactivating PAPSS2 mutations have been identified i...

Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency (21OHD) is the commonest inborn error in steroid biosynthesis. It is caused by mutations in the 21-hydroxylase gene (CYP21A2). A good genotype–phenotype correlation exists allowing for prediction of the expressed adrenal phenotype. We performed functional and structural analysis of six novel CYP21A2 variants (p.Trp22Cys; p.Asp184Asn; p.Leu198Phe; p.Val305Gly; p.His310Asn; p.Thr443Asn), i...

Congenital adrenal hyperplasia (CAH) caused by mutations in the electron donor enzyme P450 oxidoreductase (POR) is unique amongst all CAH variants in that it can be associated with ambiguous genitalia (disordered sex differentiation, DSD) both in 46,XX and 46,XY individuals. POR has a pivotal role in facilitating electron transfer from NADPH to microsomal P450 enzymes, including CYP17, which catalyses a key step in human androgen synthesis, the conversion of 17-hydroxypregneno...

P450 oxidoreductase (POR) has a pivotal role as electron donor to all cytochrome P450 enzymes that are microsomally located, i.e. CYP type II enzymes. Importantly, those include key enzymes involved in glucocorticoid and sex steroid biosynthesis such as CYP17 and CYP21. In addition, the activity of hepatic CYP enzymes involved in drug metabolism and detoxification also crucially depend on the transfer of electrons from NADPH via POR. Recently, mutations in P450 oxidoreductase ...

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis. CYP11A1 firstly converts cholesterol into 22R-hydroxycholesterol, which relies on mitochondrial steroidogenic acute regulatory protein (StAR)-mediated cholesterol import. Two further StAR-independent CYP11A1 reactions facilitate pregnenolone biosynthesis. CYP11A1 deficiency is rare and manifests with adrenal insufficiency (AI), and, in 46,XY individuals, with nor...

Congenital adrenal hyperplasia due to P450 oxidoreductase (POR) deficiency (ORD) results in disordered sex development (DSD) in individuals of both sexes. POR provides electrons to CYP17A1 thereby facilitating synthesis of the major androgen precursor dehydroepiandrosterone (DHEA). ORD disrupts this enzymatic step, resulting in deficient synthesis of 5α-dihydrotestosterone (DHT) via DHEA, readily explaining undervirilisation (46,XY DSD) in male ORD neonates. Female virili...

Cytochrome P450 side-chain cleavage enzyme (CYP11A1) catalyses the first and rate-limiting step of steroidogenesis, facilitating conversion of cholesterol to pregnenolone. Cholesterol, transported by steroidogenic acute regulatory protein (StAR) into the inner mitochondrial membrane, is converted by CYP11A1 into 22R-hydroxycholesterol. Subsequently, CYP11A1 converts 22R-hydroxycholesterol by 20alpha-hydroxylation and cleavage of the C20–C22 bond into pregnenolone. All pat...

PAPS (3′-phospho-adenosine-5′-phosphosulfate) synthases provide the cofactor PAPS for all human sulfation pathways. The cytoplasmic sulfotransferase SULT2A1 uses PAPS mainly to sulfate the androgen precursor DHEA (dehydroepiandrosterone). Apparent SULT2A1 deficiency is caused by mutations in the gene coding for PAPSS2; suggesting some form of PAPS synthase-sulfotransferase pairing. Knockdown studies within human adrenocortical NCI-295R ce...

PAPS (3′-phospho-adenosine-5′-phosphosulfate) synthases provide the cofactor PAPS for all human sulfation pathways. The cytoplasmic sulfotransferase SULT2A1 uses PAPS mainly to sulfate the androgen precursor DHEA (dehydroepiandrosterone). Apparent SULT2A1 deficiency is caused by mutations in the gene coding for PAPSS2; suggesting some form of PAPS synthase-sulfotransferase pairing. Knockdown studies within human adrenocortical NCI-295R ce...