More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones

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.

Insights Into the Peroxisomal Protein Inventory of Zebrafish

“…We also identified enzymes, which may be involved in the degradation of L-amino acids, e.g., leucine (Hmgcl, F1QTF0_DANRE) ( Table 1 and Supplementary Table S3 ). For human peroxisomal hydroxymethylglutaryl-CoA lyase (HMGCL), a role in the regulation of ketone body metabolism has been suggested ( Arnedo et al, 2019 ). Furthermore, a D. rerio L-pipecolate oxidase (Pipox) with a weak PTS1 (SSL) was identified, which likely oxidizes L-pipecolate to Δ1-piperideine-6-carboxylate ( Wanders and Waterham, 2006 ; Tables 1 , 2 and Supplementary Table S3 ).…”

Anopheles coluzzii stearoyl-CoA desaturase is essential for adult female survival and reproduction upon blood feeding

“…As silencing SCD1 increases SFA accumulation by inhibiting SFA to MUFA conversion, it is hypothesized that SFA buildup over time hinders ACC activity through a well-known feedback mechanism resulting in a drop of malonyl-CoA and increased transport of acetyl-CoA into the mitochondria for β-oxidation [ 23 ]. 3-hydroxy-3-methylglutaryl-CoA lyase (HMG-CoA lyase) that releases acetyl-CoA by breaking down leucine and fats [ 24 ] was downregulated across all time points. We speculate that HMG-CoA lyase downregulation is due to the increased flux of acetyl-CoA caused by over-activation of β-oxidation.…”

Dietary soy, pork and chicken proteins induce distinct nitrogen metabolism in rat liver

“…Leucine is an important ketogenic and essential amino acid. Leucine can be transformed into 3-methylbutyryl coenzyme A by the deamination reaction, then into 3-methylbutene-2-enoyl coenzyme A by isovaleryl coenzyme A dehydrogenase (Ivd), and finally into 3-hydroxy-3-methylpentadiene coenzyme A (HMG-CoA) by methylcrotonyl coenzyme A carboxylase 2 (Mccc2) ( Arnedo et al, 2019 ). HMG-CoA is an important intermediate product for the synthesis of cholesterol and ketones.…”