Abstract
There are three human enzymes with HMG-CoA lyase activity that are able to synthesize ketone bodies in different subcellular compartments. The mitochondrial HMG-CoA lyase was the first to be described, and catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA to acetoacetate and acetyl-CoA, the common final step in ketogenesis and leucine catabolism. This protein is mainly expressed in the liver and its function is metabolic, since it produces ketone bodies as energetic fuels when glucose levels are low. Another isoform is encoded by the same gene for the mitochondrial HMG-CoA lyase (HMGCL), but it is located in peroxisomes. The last HMG-CoA lyase to be described is encoded by a different gene, HMGCLL1, and is located in the cytosolic side of the endoplasmic reticulum membrane. Some activity assays and tissue distribution of this enzyme have shown the brain and lung as key tissues for studying its function. Although the roles of the peroxisomal and cytosolic HMG-CoA lyases remain unknown, recent studies highlight the role of ketone bodies in metabolic remodeling, homeostasis, and signaling, providing new insights into the molecular and cellular function of these enzymes.
Highlights
The mitochondrial HMG-CoA lyase was the first human HL described and its role in mammalian metabolism has been extensively studied [9]
In the 90s, the existence of another enzyme with HMG-CoA lyase activity that could produce ketone bodies in the cell was reported. It is encoded by the same gene for mitochondrial HMG-CoA lyase (mHL), HMGCL, but it is located in a different subcellular compartment, the peroxisomes [8]
The ketogenic diet has been studied as a treatment in patients with complex I deficiency, and there are a few published studies, the results show a clinical improvement of the patients [26,27]
Summary
3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) lyase (HL) catalyzes the cleavage of 3-hydroxy-3-methylglutaryl CoA into acetoacetate (AcAc) and acetyl-CoA. In the 90s, the existence of another enzyme with HMG-CoA lyase activity that could produce ketone bodies in the cell was reported. It is encoded by the same gene for mHL, HMGCL, but it is located in a different subcellular compartment, the peroxisomes [8]. In 2004, genomic databases reported a new gene, namely, HMGCLL1 with high homology to HMGCL This gene encoded a novel isoform of HL (er-cHL), which had lyase activity and was capable of synthesizing acetoacetate and acetyl-CoA [6,7]. The existence of three enzymes with HMG-CoA lyase activity and the fact that they are able to synthesize ketone bodies in different subcellular compartments is surprising. We compare for the first time, the three human isoforms of the HMG-CoA lyase from different scopes, such as metabolic, molecular biology, phylogenetic, and clinical scopes, focusing on their different features and describing their tentative roles
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
