Compartmentalised acyl-CoA metabolism and roles in chromatin regulation

Abstract

Background: Many metabolites serve as important signalling molecules to adjust cellular activities and functions based on nutrient availability. Links between acetyl-CoA metabolism, histone lysine acetylation, and gene expression have been documented and studied over the past decade. In recent years, several additional acyl modifications to histone lysine residues have been identified, which depend on acyl-coenzyme A thioesters (acyl-CoAs) as acyl donors. Acyl-CoAs are intermediates of multiple distinct metabolic pathways, and substantial evidence has emerged that histone acylation is metabolically sensitive. Nevertheless, the metabolic sources of acyl-CoAs used for chromatin modification in most cases remain poorly understood. Elucidating how these diverse chemical modifications are coupled to and regulated by cellular metabolism is important in deciphering their functional significance.

Scope of review: In this article, we review the metabolic pathways that produce acyl-CoAs, as well as emerging evidence for functional roles of diverse acyl-CoAs in chromatin regulation. Because acetyl-CoA has been extensively reviewed elsewhere, we will focus on four other acyl-CoA metabolites integral to major metabolic pathways that are also known to modify histones: succinyl-CoA, propionyl-CoA, crotonoyl-CoA, and butyryl-CoA. We also briefly mention several other acyl-CoA species, which present opportunities for further research; malonyl-CoA, glutaryl-CoA, 3-hydroxybutyryl-CoA, 2-hydroxyisobutyryl-CoA, and lactyl-CoA. Each acyl-CoA species has distinct roles in metabolism, indicating the potential to report shifts in the metabolic status of the cell. For each metabolite, we consider the metabolic pathways in which it participates and the nutrient sources from which it is derived, the compartmentalisation of its metabolism, and the factors reported to influence its abundance and potential nuclear availability. We also highlight reported biological functions of these metabolically-linked acylation marks. Finally, we aim to illuminate key questions in acyl-CoA metabolism as they relate to the control of chromatin modification.

Major conclusions: A majority of acyl-CoA species are annotated to mitochondrial metabolic processes. Since acyl-CoAs are not known to be directly transported across mitochondrial membranes, they must be synthesized outside of mitochondria and potentially within the nucleus to participate in chromatin regulation. Thus, subcellular metabolic compartmentalisation likely plays a key role in the regulation of histone acylation. Metabolite tracing in combination with targeting of relevant enzymes and transporters will help to map the metabolic pathways that connect acyl-CoA metabolism to chromatin modification. The specific function of each acyl-CoA may be determined in part by biochemical properties that affect its propensity for enzymatic versus non-enzymatic protein modification, as well as the various enzymes that can add, remove and bind each modification. Further, competitive and inhibitory effects of different acyl-CoA species on these enzymes make determining the relative abundance of acyl-CoA species in specific contexts important to understand the regulation of chromatin acylation. An improved and more nuanced understanding of metabolic regulation of chromatin and its roles in physiological and disease-related processes will emerge as these questions are answered.

Keywords: Acyl-CoA; Acylation; Compartmentalisation; Histone; Metabolism.

Figure 1

CoA World. A) Overview of metabolic pathways containing abundant acyl-CoA species. B) Chemical structures of four acyl-CoA molecules highlighted in this review and the corresponding lysine acylation marks.

Figure 2

Compartmentalisation of metabolic pathways involving succinyl-CoA and protein succinylation indicates distinct regulation of succinyl-CoA metabolism in the mitochondria, cytosol, peroxisomes and nucleus. While multiple substrates are known contributors to mitochondrial succinyl-CoA and peroxisomes can generate succinyl-CoA from oxidation of di-carboxylic acids (DCAs), the metabolic origin of precursors of succinyl-CoA in the nucleus and cytosol are not defined. Enzymes are indicated in bold type. Tapered arrows denote multiple reactions. Solid black arrows denote known reactions. Dashed arrows denote proposed or potential transformations. Abbreviations: ACOT4 (acyl-CoA thioesterase 4), BDH1 (3-hydroxybutyrate dehydrogenase 1), β-hydroxybutyrate (also known as 3-hydroxybutyrate), CACT (carnitine/Acyl-carnitine translocase), DCAs (dicarboxylic acids), GCN5 (general control of amino acid synthesis protein 5-like 2, or KAT2A), Ile (isoleucine), MCM (methylmalonyl-CoA mutase), Met (methionine), mThiolase (mitochondrial thiolase - there are several enzymes capable of performing this reaction, including ACAT1: acetyl-CoA acetyltransferase, mitochondrial, or acetoacetyl-CoA thiolase), NaDC-3 (sodium dicarboxylate transporter-3), NAD+ (nicotinamide adenine dinucleotide, oxidized form), NADH (nicotinamide adenine dinucleotide, reduced form), NAM (nicotinamide), OCFAs (odd chain fatty acids), OGDHC (oxoglutarate dehydrogenase complex), OSADPr (O-succinyl-ADP-ribose), SCOT (succinyl-CoA: 3-ketoacid CoA transferase), SDH (succinate dehydrogenase), SIRT5 (sirtuin 5), SIRT7 (sirtuin 7), SLC25A1 (solute carrier 25A1), SLC25A10 (solute carrier 25A10), SUCL (succinyl-CoA ligase), Thr (threonine), Val (valine).

Figure 3

Metabolic regulation of propionyl-CoA is annotated to the mitochondria despite histone propionylation occurring in the nucleus. Propionyl-CoA can be generated in the mitochondria through a variety of metabolic sources. It is also generated in peroxisomes from branched-chain fatty acid oxidation. Nuclear and cytosolic sources of propionyl-CoA are not defined. Enzymes are indicated in bold type. Tapered pink arrows denote multiple reactions. Solid black arrows denote known reactions. Dashed arrows denote proposed or potential transformations. Abbreviations: ACSS (acyl-CoA synthase short-chain family member, ACSS2 is localised to the cytosol, ACSS1 and 3 are localised to mitochondria), BCFAs (branched-chain fatty acids), CBP (CREB binding protein), CrAT (carnitine acyl-transferase), FASN (fatty acid synthase), GCN5(general control of amino acid synthesis protein 5-like 2, or KAT2A), Ile (isoleucine), MMSDH (methylmalonic semialdehyde dehydrogenase), MCM (methylmalonyl-CoA mutase), MCEE (methylmalonyl-CoA epimerase), Met (methionine), MOF (males absent on the first; also known as MYST1 or KAT8), NAM (nicotinamide), NAD+ (nicotinamide adenine dinucleotide, oxidised form), OCFAs (odd-chain fatty acids), OPADPr (O-propionyl-ADP-ribose), P/CAF (P300/CBP-associated factor, or KAT2B), PCC (propionyl-CoA carboxylase), SIRT1 (sirtuin 1), Thr (threonine), Val (valine), Vit. B12 (vitamin B12). (For interpretation of the references to color/colour in this figure legend, the reader is referred to the Web version of this article.)

Figure 4

Endogenous crotonoyl-CoA is generated in the mitochondria from amino acid and fatty acid catabolism, while histone crotonylation is associated with exogenous crotonate. Crotonoyl-CoA is an intermediate in tryptophan and lysine catabolism as well as fatty acid oxidation, which produces 2,3-enoyl-CoA intermediates, including crotonoyl-CoA in the mitochondria. Physiological exogenous sources of crotonate are not well defined, but addition of extracellular crotonate results in increased intracellular crotonoyl-CoA and histone crotonylation. Crotonoyl-CoA can be converted to L-β-hydroxybutyryl-CoA (also called L-3-hydroxybutyryl-CoA) by CDYL in the nucleus. Enzymes are indicated in bold type. Tapered arrows denote multiple reactions. Solid black arrows denote verified transformations. Dashed arrows denote proposed transformations. Abbreviations: CDYL (chromodomain Y-like transcription corepressor), HDAC (histone deacetylase), GCDH (glutaryl-CoA dehydrogenase), mThiolase (mitochondrial thiolase – there are several enzymes capable of performing this reaction, including ACAT1: acetyl-CoA acetyltransferase, mitochondrial or acetoacetyl-CoA thiolase), NAM (nicotinamide), NAD+ (nicotinamide adenine dinucleotide, oxidised form), NADH (nicotinamide adenine dinucleotide, reduced form), OGDHC (oxoglutarate dehydrogenase complex), OCADPr (O-crotonyl-ADP-ribose), SIRT1, 2, 3 (sirtuin 1, 2, 3).

Figure 5

Butyryl-CoA can be generated from the microbial fermentation product butyrate and as an intermediate in fatty acid synthesis and oxidation in the mitochondria. Histone butyrylation can be catalysed by a variety of acetyl-transferases and may be removed by sirtuin 1, 2 or 3. Enzymes are indicated in bold type. Tapered arrows denote multiple reactions. Solid black arrows denote verified transformations. Dashed arrows denote proposed transformations. Abbreviations: ACSS (acyl-CoA synthetase short-chain family member- ACSS2 is localised to the cytosol, ACSS1 and 3 are localised to mitochondria), CACT (carnitine/acyl-carnitine translocase), CBP (CREB-binding protein), CrAT (carnitine acyl-transferase), GCN5 (general control of amino acid synthesis protein 5-like 2, or KAT2A), mFASN (mitochondrial fatty acid synthase), MOF (males absent on the first; also known as MYST1 or KAT8), NAD+ (nicotinamide adenine dinucleotide, oxidised form), NADH (nicotinamide adenine dinucleotide, reduced form), NAM (nicotinamide), OBADPr (O-butyryl-ADP-ribose), NatA (N-terminal acetyl-transferase A), P/CAF (P300/CBP-associated factor, or KAT2B), PCC (propionyl-CoA carboxylase), SCAD (short-chain acyl-CoA dehydrogenase), SIRT1, 2, 3 (sirtuin 1, 2, 3), Tip60 (60 kDa Tat-interactive protein, or KAT5).