Non-traditional metabolic pathways of adrenal steroids
Abstract
Metabolic pathways are reconstructed from biochemical evidence to conceptualize the predominant route to important biomolecules. Pathways have heuristic value in their capacity to explain the metabolic derangements in genetic diseases of enzyme deficiencies and during pharmacologic inhibition of these enzymes. Implicit in the description of these pathways is the potential existence of alternate routes, variable order of reactions, and the inevitable by-products generated by incomplete efficiencies and competing enzymes. This chapter will consider alternate fates encountered by steroid hormone precursors in the adrenal gland, the variables influencing flux through these secondary pathways, and the significance of these diversions in health and disease.
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Genetic males with ambiguous genitalia usually have disorders in the classical androgen biosynthesis pathway from cholesterol via pregnenolone to DHEA and Δ4-androstene-3,17-dione.
“Genetic males with incompletely developed (ambiguous) genitalia usually have disorders in the classical pathway of androgen biosynthesis which proceeds from cholesterol via pregnenolone to form dehydroepiandrosterone and Δ4-androstene-3,17-dione [33, 102].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
AKR1C3 converts Δ4-androstene-3,17-dione to testosterone in the classical androgen biosynthesis pathway.
“In this pathway AKR1C3 converts Δ4-androstene-3,17-dione to testosterone”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
Androsterone is converted to 3α-Diol by AKR1C3, and 3α-Diol is the immediate precursor of 5α-DHT.
“Androsterone is converted to 3α-Diol by AKR1C3 which is the immediate precursor of 5α-DHT.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
In the backdoor pathway, AKR1C2 and AKR1C4 catalyze reduction of 5α-pregnane-3,20-dione to allopregnanolone, the precursor of androsterone.
“In this pathway, AKR1C2 and AKR1C4 catalyze the reduction of 5α-pregnane-3,20-dione to yield allopregnanolone which is the precursor of androsterone.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
AKR1C3 converts 5α-androstane-3,17-dione to 5α-DHT in the alternative pathway.
“and in the alternative pathway it converts 5α-androstane-3,17-dione to 5α-DHT [102].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
Mutations in AKR1C2 and AKR1C4 in DSD patients suggest that the backdoor pathway, converting progesterone to 5α-DHT, plays a crucial role in fetal androgen biosynthesis.
“However, mutations in AKR1C2 and AKR1C4 in these patients suggest that in fetal development the backdoor pathway [33, 102], which involves the conversion of progesterone into 5α-DHT plays a crucial role in androgen biosynthesis.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [102]
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- Authors
- Auchus, R. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Auchus, Richard J.
- ORCID
- Auchus, Richard J.
- Venue
- Reviews in Endocrine and Metabolic Disorders
- Published
- 2008-08-22
- Volume
- 10
- Issue
- 1
- Pages
- 27-32
- ISSN
- 1389-9155 (ISSN-L)
- 1573-2606
- OpenAlex
- W2090139787
- Cited by
- 17
- References
- 48
- Citations by year
- 2026: 1 · 2025: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2014: 2 · 2013: 2
- FWCI
- 0.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Reviews in Endocrine and Metabolic Disorders (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Welch Foundation
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- adrenal steroid metabolism, enzyme deficiency, metabolic flux, adrenal gland
- MeSH terms
- Adrenal Glands, Adrenal Hyperplasia, Congenital, Animals, Female, Humans, Male, Pregnancy, Steroid 21-Hydroxylase, Steroids, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Metabolic Networks and Pathways
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