ABSTRACT
Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown HMG-CoA is a reactive metabolite that can non-enzymatically modify proteins and impact their activity. Therefore, we predicted that inhibition of HMGCR by statins might increase HMG-CoA levels and protein modifications. Upon statin treatment, we observe a strong increase in HMG-CoA levels and modification of only a single protein. Mass spectrometry identifies this protein as fatty acid synthase (FAS), which is modified on active site residues and, importantly, on non-lysine side-chains. The dynamic modifications occur only on a sub-pool of FAS that is located near HMGCR and alters cellular signaling around the ER and Golgi. These results uncover communication between cholesterol and lipid biosynthesis by the substrate of one pathway inhibiting another in a rapid and reversible manner.
Subject(s)
Cardiovascular Diseases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Cardiovascular Diseases/prevention & control , Cholesterol/metabolism , Fatty Acid Synthases , Humans , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Mevalonic Acid/metabolismABSTRACT
Fatty acid synthesis (FAS) in mitochondria produces a key metabolite called lipoic acid. However, a new study by Van Vranken et al.[1] (Mol. Cell 2018;71:567-580) shows that mitochondrial FAS regulates the assembly of oxidative phosphorylation complexes, thereby functioning as a nutrient sensor for mitochondrial respiration.
Subject(s)
Acetyl Coenzyme A/metabolism , Acyl Carrier Protein/metabolism , Eukaryota/metabolism , Fatty Acids/metabolism , Mitochondria/metabolism , RespirationABSTRACT
In recent years, our understanding of the scope and diversity of protein post-translational modifications (PTMs) has rapidly expanded. In particular, mitochondrial proteins are decorated with an array of acyl groups that can occur non-enzymatically. Interestingly, these modifying chemical moieties are often associated with intermediary metabolites from core metabolic pathways. In this Review, we describe biochemical reactions and biological mechanisms that activate carbon metabolites for protein PTM. We explore the emerging links between the intrinsic reactivity of metabolites, non-enzymatic protein acylation, and possible signaling roles for this system. Finally, we propose a model of 'carbon stress', similar to oxidative stress, as an effective way to conceptualize the relationship between widespread protein acylation, nutrient sensing, and metabolic homeostasis.
