The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR; E.C. is an endoplasmic reticulum-bound, cytoplasmic protein. HMGCR converts HMG-CoA to mevalonate, the key precursor for the synthesis of cholesterol and isoprenoids. These mevalonate-derived metabolites coordinate diverse cellular and molecular processes, with various developmental and pathological implications. Cholesterol, a major metabolite of HMGCR pathway, is an essential developmental metabolite. cholesterol is a major component of cell membranes, regulating membrane fluidity and permeability, and it is the precursor molecule of other steroids, including bile salts, steroid hormones, and vitamin D. An additional developmental role for cholesterol is through its covalent modification of the morphogenic protein sonic hedgehog (SHH) specifically at the carboxyl end of the immature protein. SHH signalling plays a vital role in craniofacial development, limb and digit morphogenesis, brain development, as well as several regenerative processes. Modulation of HMGCR activity can concomitantly affect cholesterol-mediated covalent modification of SHH processing and the transcription of target genes, which further highlights a developmental requirement for both maternal and embryonic HMGCR.


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