SRD5A3 Is Required for Converting Polyprenol to Dolichol and Is Mutated in a Congenital Glycosylation Disorder

Neurogenetics Laboratory, Institute for Genomic Medicine, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
Cell (Impact Factor: 32.24). 07/2010; 142(2):203-17. DOI: 10.1016/j.cell.2010.06.001
Source: PubMed


N-linked glycosylation is the most frequent modification of secreted and membrane-bound proteins in eukaryotic cells, disruption of which is the basis of the congenital disorders of glycosylation (CDGs). We describe a new type of CDG caused by mutations in the steroid 5alpha-reductase type 3 (SRD5A3) gene. Patients have mental retardation and ophthalmologic and cerebellar defects. We found that SRD5A3 is necessary for the reduction of the alpha-isoprene unit of polyprenols to form dolichols, required for synthesis of dolichol-linked monosaccharides, and the oligosaccharide precursor used for N-glycosylation. The presence of residual dolichol in cells depleted for this enzyme suggests the existence of an unexpected alternative pathway for dolichol de novo biosynthesis. Our results thus suggest that SRD5A3 is likely to be the long-sought polyprenol reductase and reveal the genetic basis of one of the earliest steps in protein N-linked glycosylation.

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Available from: Vincent Cantagrel
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    • "The steroid products of the 5α-Rs pathways undergo further metabolism by the 3α-hydroxy-steroid dehydrogenase (3α-HSD) to produce a host of active neurosteroids with important physiological function, in many tissues including the central nervous system (CNS) (Fig. 1) [1,2]. In addition, synthesis of dolichol from polyprenol was recently shown to require the activity of the 5α-R type 3 [3]. Since dolichol phosphate is critical in N-glycosylation of membrane proteins, inhibition of the activity of 5α-R type 3 may have undesirable effects as a result of attenuation of this and other biochemical pathways important in modulating cellular function [4]. "
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    ABSTRACT: With aging, abnormal benign growth of the prostate results in benign prostate hyperplasia (BPH) with concomitant lower urinary tract symptoms (LUTS). Because the prostate is an androgen target tissue, and transforms testosterone into 5α-dihydrotestosterone (5α-DHT), a potent androgen, via 5α-reductase (5α-R) activity, inhibiting this key metabolic reaction was identified as a target for drug development to treat symptoms of BPH. Two drugs, namely finasteride and dutasteride were developed as specific 5α-reductase inhibitors (5α-RIs) and were approved by the U.S. Food and Drug Administration for the treatment of BPH symptoms. These agents have proven useful in the reducing urinary retention and minimizing surgical intervention in patients with BPH symptoms and considerable literature exists describing the benefits of these agents. In this review we highlight the adverse side effects of 5α-RIs on sexual function, high grade prostate cancer incidence, central nervous system function and on depression. 5α-Rs isoforms (types 1-3) are widely distributed in many tissues including the central nervous system and inhibition of these enzymes results in blockade of synthesis of several key hormones and neuro-active steroids leading to a host of adverse effects, including loss of or reduced libido, erectile dysfunction, orgasmic dysfunction, increased high Gleason grade prostate cancer, observed heart failure and cardiovascular events in clinical trials, and depression. Considerable evidence exists from preclinical and clinical studies, which point to significant and serious adverse effects of 5α-RIs, finasteride and dutasteride, on sexual health, vascular health, psychological health and the overall quality of life. Physicians need to be aware of such potential adverse effects and communicate such information to their patients prior to commencing 5α-RIs therapy.
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    • "The 46, XY disorders of sex development (DSD) are presently classified in three main categories [1]: disorders of gonad development such as gonadal dysgenesis, disorders of androgen biosynthesis and metabolism and disorders related to androgen sensitivity (the androgen insensitivity syndrome, AIS). Within the second category, genetic causes have been identified, such as loss of function mutations of the LH receptor gene (LHCGR), 17β hydroxysteroid dehydrogenase deficiency type 3, related to mutations of the HSD17B3 gene and loss of function mutations of the SRD5A2 gene, responsible for 5α-reductase type 2deficiencywhich is one of the three 5α-reductase isoforms expressed in humans [2]. In the third category, androgen receptor (AR) mutations have been identified in patients with mild, partial or complete androgen insensitivity syndromes (AIS) [1]. "
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    • "In 5-AR2 deficient men, Thiele et al.31 reported that 5-AR1 may play a critical role in the masculinization of 5-AR2 deficient men. Cantagrel et al.16 reported that patients with mutations in SRD5A3 exhibited a multisystemic syndrome with psychomotor delay, cerebellar vermis hypoplasia and eye malformation. "
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