Hydroxymethylglutaryl-CoA synthase, cytoplasmic

HMGCS1 (hydroxymethylglutaryl-CoA synthase, cytoplasmic) catalyzes the first committed step of cholesterol synthesis by condensing acetyl-CoA with acetoacetyl-CoA to form HMG-CoA, which is subsequently converted to mevalonate by HMG-CoA reductase (UniProt: Q01581). This 57 kDa enzyme is localized to the cytoplasm and plays a central role in lipid biosynthesis pathways.

HMGCS1 is involved in mevalonate metabolism and cholesterol homeostasis, processes essential for maintaining neuronal membrane integrity and function. While no primary disease associations are documented in UniProt for this protein, dysregulation of cholesterol synthesis pathways has been implicated in neurodegenerative processes.

In Alzheimer's disease, HMGCS1 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change is −0.97 across quantified subcellular fractions (P2, P3, S2, S3), indicating reduced protein abundance. This downregulation of a key cholesterol biosynthetic enzyme may reflect impaired lipid metabolism and reduced neuronal capacity for membrane synthesis in AD pathology.