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Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL)
- Target
- NSDHL
- Molecular classification
- Enzyme, Short-chain dehydrogenase/reductase family (SDR), Oxidoreductase (acting on CH-OH group, with NAD(P)+ as acceptor)
01
Overview
Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (NSDHL) is an essential enzyme in human cholesterol biosynthesis that catalyzes the NAD(P)+-dependent oxidative decarboxylation of C4 methyl groups from 4-alpha-carboxysterols, a key post-squalene step. Localized to the endoplasmic reticulum and Golgi apparatus, NSDHL additionally regulates trafficking of the epidermal growth factor receptor (EGFR), impacting signal transduction in cancer cells. Mutations in NSDHL cause CHILD syndrome, resulting in severe defects in lipid metabolism. NSDHL is a promising therapeutic target for cholesterol-related diseases and certain cancers, especially where EGFR signaling is dysregulated.
- Other names
- NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHLNAD(P)-dependent steroid dehydrogenase-like proteinSDR31E1H105E3Protein H105e3XAP1043-beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating)Epididymis secretory sperm binding protein
02
Mechanism of action
Inhibitors bind the coenzyme (NAD(P)+) binding site, preventing oxidative decarboxylation of sterol intermediates, suppressing cholesterol synthesis and downstream EGFR signaling. Synergy with EGFR inhibition leading to enhanced tumor cell death
03
Biological functions
Cholesterol biosynthesis (post-squalene pathway)Cellular lipid metabolismSignal transduction (via EGFR trafficking regulation)Removal of C4 methyl groups in sterol intermediates
04
Disease associations
Cancer (especially as a modulator of EGFR-driven cell growth, and a potential target in carcinoma therapy)X-linked dominant disorders of lipid metabolism (CHILD syndrome)Lipid metabolism disorders
05
Safety considerations
Potential disruption of systemic cholesterol synthesis resulting in adverse effects such as dermatological, hepatic, and developmental abnormalitiesLethality of NSDHL gene mutations in males due to X-linked dominant inheritanceOff-target effects on lipid metabolism
06
Interacting drugs
Erlotinib hydrochloride (EGFR inhibitor with synergistic antitumor effects when combined with NSDHL inhibitor)
07
Biomarkers
Mutations in NSDHL gene for diagnosis of CHILD syndromeExpression/activity levels of NSDHL as efficacy markers in cholesterol biosynthesis-targeted therapiesChanges in EGFR signaling after NSDHL inhibition as pharmacodynamic biomarker
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