Lysine malonylation

Lysine malonylation (Kmal, maK), protein malonylation or malonylation, is a reversible post-translational modification (PTM) in eukaryotic and prokaryotic cells, in which a malonyl group (–CO–CH2–COOH) is added to a lysine (K) residue of a protein.[1][2][3] It belongs to the family of acidic acyl modifications, such as succinylation and glutarylation.[4] First identified in 2011 by Peng et al., it has since emerged as an evolutionarily conserved mechanism that is dynamically regulated under diverse biological and cellular conditions, such as stress responses, metabolic changes, and genetic mutations, and can alter protein charge, structure, and function.[5][6][3] These molecular effects extend to pathways of glucose and fatty acid metabolism, histone-mediated gene regulation, and are increasingly linked to immune regulation, angiogenesis, and metabolic diseases such as obesity and type 2 diabetes.[7] While its biological relevance is increasingly recognized, many aspects of its regulatory mechanisms and functional roles remain to be elucidated to realize its therapeutic potential.[7]

Chemical properties

Through the covalent attachment of a malonyl group to the ε-amino group of lysine residues, the lysine side chain shifts in charge from +1 to −1 at physiological pH due to the negatively charged carboxyl group of the malonyl moiety.[8][1][4] This complete reversal of charge is assumed to disrupt ionic interactions between the normally positively charged lysine side chain and negatively charged components of nucleotides, proteins, and small molecules, and to alter the protein's own structure.[4] The number of malonylation sites per protein can vary widely, as shown in mouse liver where 50.5% of malonylated proteins carried only a single site, while others had two or more, with the most heavily modified enzyme being carbamoyl‑phosphate synthetase 1 (CPS1) of the urea cycle with 31 sites.[9]

Position within other lysine acylations

Malonylation, like lysine acetylation, is an acyl lysine modification but, unlike acetylation, which neutralizes lysine's positive charge, it introduces a negative one, placing it among the acidic acylations alongside methylmalonylation, succinylation, glutarylation, 3‑hydroxy‑3‑methylglutarylation, 3‑methylglutaconylation, and 3‑methylglutarylation.[4][10][11] In size, malonylation (three carbons) is bulkier than acetylation (two carbons) but smaller than succinylation (four carbons) and glutarylation (five carbons).[4] As a result, these acidic acyl modifications are expected to exert a greater impact on protein structure and function than acetylation at the same lysine site.[9]

Each modification arises from a distinct acyl‑CoA donor: acetylation from acetyl‑CoA, succinylation from succinyl‑CoA, malonylation from malonyl‑CoA, methylmalonylation from methylmalonyl-CoA and glutarylation from glutaryl‑CoA.[12][5][11][13] Malonyl‑CoA is produced in cytosol and mitochondria by acetyl‑CoA carboxylase (ACC) and, in mitochondria, also by acyl-CoA synthetase family member 3 (ACSF3);[14] succinyl‑CoA stems from the TCA cycle and amino acid catabolism;[1][5] glutaryl‑CoA from amino acid catabolism;[1] and methylmalonyl‑CoA from amino acid and odd‑chain fatty acid metabolism, accumulating in vitamin B12 deficiency and methylmalonic acidemias.[11] Malonyl‑CoA is far less reactive toward proteins than succinyl‑CoA or glutaryl‑CoA because, like acetyl‑CoA, its shorter carbon chain cannot support the intramolecular catalysis needed to form reactive cyclic anhydride intermediates, which in turn enable protein acylation over a broader pH range.[15] Malonyl, succinyl, and glutaryl groups are removed by Sirtuin 5 (SIRT5), which shows little activity toward acetylation.[4]

Malonylation occurs mainly in mitochondria but also in the cytosol and nucleus, with ~58% of malonylated proteins in mouse liver mitochondrial compared to an even distribution in human fibroblasts, whereas succinylation and glutarylation are predominantly but not exclusively mitochondrial.[16][4] The relative abundance of these acylations reflects cellular donor availability, with acetylation most common, succinylation reaching 10–30% of acetylation levels, malonylation occurring at least tenfold lower, and glutarylation detected only in trace amounts.[10] In terms of overlaps, a study in mouse liver cells found that 56% of mitochondrial malonylation sites overlapped with succinylation, while 44% were unique to malonylation (neither succinylated nor acetylated).[9] Conversely, 86% of succinylation sites overlapped with at least one of these other acylations, and only 6% of sites carried all three modifications, mainly in proteins involved in fatty acid oxidation, glutaryl‑CoA degradation, and ketogenesis.[9] The distinct distribution of malonylation, its specific target proteins, and the individual lysine sites it modifies, suggest a unique role among lysine acyl modifications in cellular regulation.[9]

Selected lysine acyl modifications
Acetylation Malonylation Methylmalonylation Succinylation Glutarylation
Functional group Chemical formula C2H30 C3H2O4 C4H5O3 C4H4O4 C5H6O4
Condensed structural formula –CO–CH3 –CO–CH2–COOH –CO–CH(CH3)–COOH –CO–(CH2)2–COOH –CO–(CH2)3–COOH
Bulkiness Two-carbon group[4] Three-carbon group[4] Four-carbon group Four-carbon group[4] Five-carbon group[13]
Charge shift +1 → 0[4] +1 → -1[4][11]
Donor Acetyl-CoA[4] Malonyl-CoA[5] Methylmalonyl-CoA[11] Succinyl-CoA[12] Glutaryl-CoA[4]
Frequency Acetyl-CoA < Succinyl-CoA < Malonyl-CoA < Glutaryl-CoA[10]
Non-enzymatic acylation: Reactivity No anhydride ring formation[15] No anhydride ring formation[15] Unknown Highly reactive five‑membered cyclic anhydride intermediate[15] Highly reactive six‑membered cyclic anhydride intermediate[15]
Enzymatic deacylation: Enzymes (Eraser) Global: Sirtuin 5[4][11]
Pathways

Malonyl-CoA as donor

Main article: Malonyl-CoA

Malonyl-CoA, the donor for lysine malonylation, is membrane-impermeable and must be synthesized locally in each cellular compartment.[19]

  • In the cytosol, acetyl-CoA carboxylase (ACC) generates malonyl-CoA from acetyl-CoA and CO2 and is responsible for the majority of the cellular malonyl-CoA pool.[20] The amount of malonyl-CoA in the cytosol is tightly regulated by the opposing activities of ACC and malonyl-CoA decarboxylase (MCD), which catalyzes the reverse reaction to produce acetyl-CoA and CO2.[16] Cytosolic malonyl-CoA plays a key role in regulating fatty acid metabolism.[20] Although malonyl-CoA itself cannot enter mitochondria, malonate produced through non-enzymatic hydrolysis of cytosolic malonyl-CoA may cross membranes and contribute to the mitochondrial malonyl-CoA pool.[20]
  • In mitochondria, the malonyl-CoA pool is generated by acyl-CoA synthetase family member 3 (ACSF3), which catalyzes the thioesterification of malonate and CoA, and by a mitochondrial isoform of acetyl-CoA carboxylase 1 (mtACC1), which produces malonyl-CoA through the carboxylation of acetyl-CoA and CO2.[14] Complementing these synthetic activities, MCD likeweise operates in mitochondria, where it converts malonyl-CoA back to acetyl-CoA and CO2.[19] Mitochondrial malonyl‑CoA is essential for local protein malonylation as well as for mitochondrial fatty acid synthesis (mtFAS).[19][14]
  • In the nucleus, malonyl-CoA is synthesized by ACC1, which is mainly cytoplasmic, suggesting a local and possibly unconventional function.[1]

The extent of malonylation increases with malonyl‑CoA availability particularly under conditions such as metabolic stress or enzyme deficiencies, for example malonyl‑CoA decarboxylase deficiency.[16][21]

Mechanism

Non-enzymatic malonylation

The non-enzymatic malonylation mechanism involves the spontaneous transfer of a malonyl group from malonyl‑CoA to lysine residues on proteins, without the need for an enzyme.[8] This reaction is driven by the intrinsic electrophilicity of malonyl‑CoA, a hyper‑reactive thioester whose electron‑withdrawing carboxyl group increases the susceptibility of its thioester bond to nucleophilic attack by deprotonated lysine side chains.[8] In the mitochondrial matrix, conditions are especially favorable for non‑enzymatic malonylation due to the alkaline pH, which promotes lysine deprotonation.[1] In compartments with near‑neutral pH, such as the cytosol or nucleus, lysine residues are less reactive, and malonylation in these locations may rely more on enzymes, suggesting that both mechanisms contribute to the overall malonylation pattern in cells.[1]

Enzymatic malonylation

The enzymes that catalyze malonylation, known as malonyltransferases, have not yet been definitively identified.[1] Structural similarities between acetyl-CoA and malonyl-CoA suggest that some lysine acetyltransferases (KATs) may also catalyze malonylation.[4] KAT2A (GCN5) has been experimentally linked to histone malonylation and is currently the strongest candidate, while p300 is another proposed candidate and is known to mediate other acyl modifications such as crotonylation.[1][3]

Demalonylation

The removal of malonylation is catalyzed by Sirtuin 5 (SIRT5), a class III histone deacetylase that requires NAD+ for activity but is inhibited by nicotinamide.[5] SIRT5 is globally expressed in mitochondrial, cytoplasmic, and nuclear compartments, and can also remove other negatively charged acyl modifications, including succinyl, glutaryl and methylmalonyl groups, while exhibiting little activity toward acetyl groups.[4][11] It catalyzes the removal of the malonyl group in the following reaction:[4]

malonyl-lysine-protein + NAD+ → lysine-protein + O-malonyl-ADP-ribose + nicotinamide

Proteomic profiling of mouse liver revealed that SIRT5 regulates proteins involved in glycolysis, gluconeogenesis, fatty acid oxidation, and the urea cycle.[9] Of all identified malonyl‑lysine sites, about 16% are regulated by SIRT5, with the majority of these regulated proteins (73%) containing only a single malonylated lysine site.[9] The moderate effect of SIRT5 knockdown on lysine malonylation suggests the presence of additional, unidentified demalonylases.[2] Additionally, it has been proposed that demalonylases and deacetylases may function less as novel regulatory enzymes and more as a protein quality‑control mechanism.[20]

Malonylated proteins

Proteomic analysis revealed malonylated proteins were enriched in pathways related to glucose and fatty acid metabolism, as well as the urea cycle, involving both mitochondrial and cytosolic enzymes.[2][9] Malonylation was also detected on nuclear proteins such as histone H2B.[1]

Below is a list of selected proteins that have been experimentally verified to undergo malonylation:

Clinical relevance

Combined malonic and methylmalonic aciduria (CMAMMA)

Combined malonic and methylmalonic aciduria (CMAMMA) is caused by mutations in the ACSF3 gene, which encodes acyl-CoA synthetase family member 3 (ACSF3), a mitochondrial enzyme that converts malonate and methylmalonate into their respective CoA derivatives.[24] In the liver, expression of ACSF3 and mitochondrial protein malonylation show feeding-dependent daily rhythms, with malonylation peaking shortly after ACSF3 expression and independently of the core circadian clock.[23] The loss of ACSF3 activity in this tissue reduces mitochondrial malonylation and disrupts key metabolic pathways such as glycolysis, gluconeogenesis, fatty acid oxidation and NADPH metabolism, ultimately impairing energy balance.[23]

Malonic aciduria

Malonic aciduria is caused by mutations or deletions in the MLYCD gene, which encodes for malonyl-CoA decarboxylase (MCD), an enzyme required for the conversion of malonyl-CoA to acetyl-CoA.[25] The loss of MCD activity leads to accumulation of malonyl-CoA and a marked increase in lysine malonylation.[16] Proteomic and functional analyses have shown that this hypermalonylation impairs mitochondrial respiration and reduces fatty acid oxidation capacity, suggesting a direct role for protein malonylation in the disease's metabolic dysfunction.[16] Clinical similarity between MCD and ACSF3 defects suggest their involvement in a shared malonate detoxification pathway.[19]

Histone malonylation and aging

Malonylation also occurs on nuclear proteins, including histones, where it regulates chromatin-associated processes.[1] Histone malonylation has been shown to increase ribosomal RNA (rRNA) expression and nucleolar size, both of which are features associated with cellular aging.[1] Aged mouse tissues exhibit globally increased malonylation, potentially due to elevated expression of acetyl-CoA carboxylase and reduced activity of the deacylase SIRT5, which depends on declining NAD+ levels.[1] These findings suggest a role for histone malonylation in the epigenetic regulation of aging processes.[1]

Type 2 diabetes & obesity

In type 2 diabetes, lysine malonylation is significantly elevated in liver tissue, as shown in obese mouse models such as db/db and ob/ob mice.[2] Many of the affected proteins are involved in glucose and lipid metabolism, and malonylation of glycolytic enzymes has been shown to suppress their activity, leading to reduced glycolytic flux.[2][9] Six of the ten glycolytic enzymes are malonylated at sites regulated by the demalonylase SIRT5, which counteracts this inhibition and may serve as a therapeutic target, along with other yet unidentified enzymes that regulate malonylation.[9][2]

Immune regulation

In resting macrophages, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) binds to inflammatory mRNAs such as TNFα and suppresses their translation.[3] In activated macrophages, lysine malonylation functions as a regulatory signal during inflammatory responses.[3] Inflammatory stimulation with lipopolysaccharide (LPS) increases cytosolic malonyl-CoA levels and leads to malonylation of GAPDH at lysine 213.[3] Malonylation disrupts this binding, thereby promoting translation of pro-inflammatory cytokines like TNFα.[3] These findings establish lysine malonylation as a link between cellular metabolism and immune activation.[3]

Angiogenesis

Inhibition of fatty acid synthase (FASN) increases malonyl-CoA levels in endothelial cells, leading to lysine malonylation of mTOR at lysine 1218.[26] This impairs the kinase activity of mTOR complex 1, which reduces endothelial proliferation and ultimately leads to impaired angiogenesis.[26] The effect was seen in both normal vessel development and disease-related angiogenesis, such as retinal neovascularization in a mouse model of retinopathy of prematurity (ROP).[26] These findings link malonylation to angiogenic regulation via mTOR signaling.[26]

Research

Malonyllysine is chemically unstable and can decarboxylate to acetyllysine upon heating, which complicates its analysis and may lead to misidentification.[27] In tandem mass spectrometry, this reaction is associated with a characteristic 44 Da loss corresponding to CO2 release.[5] To overcome this, a stable tetrazole-based malonyllysine isostere was developed that resists such decomposition.[27] It is compatible with peptide synthesis and shows reduced but detectable recognition by malonyl-specific antibodies and SIRT5, allowing studies of malonylation without decarboxylation artifacts.[27]

See also

References

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