Studies have shown that active metabolites can impact all aspects of omics research (genomics, epigenomics, transcriptomics, and proteomics). Under this framework, metabolites mainly regulate the functions of DNA, RNA, and protein in two ways: chemical modification and metabolite-macromolecule interactions.
Metabolite biological macromolecules play an important driving role in valence modification (DNA, RNA methylation, and post-translational protein modification). These dynamic chemical modifications can also have a significant impact on cell function.
The figure shows the role played by the intermediate products of the tricarboxylic acid cycle in the chemical modification of macromolecules. There are at least a dozen small molecules involved in the post-translational modification of proteins, which can be covalently bound to different amino acids in enzymatic reactions, such as acetylation of lysine, palmitoylation of cysteine, etc. . It should be pointed out that acetylation can occur in the form of a non-enzymatic response, but its function is unclear. In addition, some metabolites can also participate in other post-translational modifications, such as succinylation and glycosylation of arginine.
Small molecule metabolites can also control the anti-inflammatory response through the alkylation of cysteine residues. As shown in the figure above, itaconic acid (Itaconate) is a small, branched-chain fatty acid with anti-inflammatory activity. Itaconate can directly alkylate the cysteine residues of KEAP1. KEAP1 is the primary negative regulator responsible for the degradation of NRF2. Alkylation can inhibit the activity of KEAP1, thereby increasing the activity of NRF2 and ultimately promoting the expression of antioxidant and anti-inflammatory genes.
Small molecule metabolites can also control protein homeostasis through poly ADP ribosylation modification of proteasome components. As shown in the figure above, proteasome PI31 undergoes ADP ribosylation under the action of TNKS to promote the assembly of proteasome 26S and ultimately promote the increase of proteasome activity.
Lysine glut arylation is another way for small molecule metabolites to control enzyme activity. As shown in the figure above, lysine and tryptophan are the sources of glutaryl-CoA, which can make the rate-limiting enzyme CPS1 in the urea cycle glutaryl lysine, reduce enzyme activity, and cause hyperammonemia.
In addition, for some proteins, the methylation of S-adenosylmethionine (SAM) can be used to methylate its lysine residues. SAM is a methyl donor for DNA, histone, and RNA methylation and can regulate gene expression at the genome, epigenome, and transcriptome levels. SAM can also mediate the methylation of some non-histone proteins to regulate their functions.
Methylation is the essential modification method of DNA. The process involves the transfer of methyl groups from SAM to cytosine. DNA methylation can regulate the accessibility of DNA and is an essential regulator of gene expression.
SAM and other metabolites, such as glycine, pyruvate, galactose, and threonine, can also be used as cofactors for RNA post-transcriptional modification-related enzymes. These RNA modifications can be used as sensors to regulate metabolic rate (such as oxygen consumption) and protein synthesis, but their role has yet to be fully revealed.
The histone modifications that occur under the action of enzymes, such as lysine acetylation, lysine and arginine methylation, and serine phosphorylation, are key control factors of the epigenome, which directly affect gene expression and chromosome packaging, And DNA repair.
The non-covalent interaction between metabolites and macromolecules is the second mode by which metabolites regulate cell activity. Classic examples are the competitive binding (inhibition) of metabolites to the active site of an enzyme and the binding of metabolites to areas other than the active site, which causes changes in enzyme activity (alternative). These concepts apply to enzymes, regulatory rRNAs, proteins, and other molecules.
G protein-coupled receptors (GPCRs) are the most intensively studied signaling molecules activated by metabolites, and they are one of the first proteins identified as drug targets. GPCR91 in mice is also called succinate receptor 1, which can control blood pressure after succinate activation. As shown in the figure above, many fatty acids can activate GPCR40 (free fatty acid receptor 1). For example, palmitate hydroxystearic acid (PAHSA) activates GPCR40 to induce calcium ion conduction, causing insulin and glucagon-like peptide-1 (GLP1) Increase, thereby improving glucose tolerance. Therefore, PAHSA can be used as a potential anti-diabetic drug. The binding of metabolites to these receptors triggers highly specific signal transduction, which leads to specific cellular activation of the signal transduction network.
Metabolites can also bind transcription factors to regulate gene expression. For example, phytoestrogens in food can cause atypical activation of estrogen receptors, which control the expression of genes related to cell metabolism and cell proliferation. Through this mechanism, phytohormones can interfere with the treatment of breast cancer.
At the level of transcription and translation, metabolites can function through riboswitches. Metabolites controlling riboswitches include lysine, glutamine, cobalamin, thiamine pyrophosphate (TPP), and purines. In this process, metabolites bind to different mRNA regions, change the mRNA conformation and ultimately regulate protein translation.
Metabolites can also promote the assembly of polymer proteins. As shown in the figure, bacterial ATP-1-phosphate glucose uracil transferase galF can assemble into multimers (pentamers or hexamers) in the presence of ATP.
Rinschen M M, Ivanisevic J, Giera M, et al. Identification of bioactive metabolites using activity metabolomics. Nature Reviews Molecular Cell Biology, 2019, 20(6): 353-367.
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