Ketogenesis Impact on Liver Metabolism Revealed by Proteomics of Lysine β-hydroxybutyrylation

Koronowski, Kevin B.; Greco, Carolina; Huang, He; Kim, Jin-Kwang; Fribourgh, Jennifer L.; Crosby, Priya; Partch, Carrie L.; Qiao, Feng; Zhao, Yingming; Sassone–Corsi, Paolo

doi:10.1101/2021.01.21.427645

Cited by 12 publications

(18 citation statements)

References 67 publications

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“…17 However, during fasting and intense exercise it quickly reaches concentrations of 1-2 mM and can further rise up to 20 mM in certain pathological states, such as diabetes. 37 Apart from serving as an energy carrier, D-bhb is posttranslationally installed on lysine side chains of proteins in the nucleus, cytosol, and mitochondria, which provides a further link between metabolism and proteome expansion. 5,11,37 Zhao and coworkers hypothesized that D-b-hydroxybutyrylysine [K(D-bhb)] PTMs could be installed on histones by transferases using activated D-bhb-CoA (Figure 3A).…”

Section: D-b-hydroxybutyrylationmentioning

confidence: 99%

Chiral Posttranslational Modification to Lysine epsilon-Amino Groups

Moreno–Yruela

Bæk

Monda

et al. 2022

Preprint

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The sophistication of proteomic analysis has revealed that protein lysine residues are posttranslationally modified by a variety of acyl groups. Protein lysine acetylation regulates metabolism, gene expression, and microtubule formation and has been extensively studied; however, the understanding of the biological significance of other acyl posttranslational modifications (PTMs) is still in its infancy. The acylation of lysine residues is either mediated by acyltransferase ‘writer’ enzymes or through non-enzymatic mechanisms and hydrolase enzymes, termed ‘erasers’, cleave various acyl PTMs to reverse the modified state. We have studied the human lysine deacylase enzymes, comprising the 11 Zn2+-dependent histone deacetylases (HDACs) and the 7 NAD+-consuming sirtuins (SIRTs), over the last decade. We have thus developed selective inhibitors and molecular probes as well as studied the acyl substrate scope of each enzyme using chemically synthesized peptide substrates and photo-crosslinking probes. Recently, we have turned our attention to lysine PTMs containing a stereogenic center, such as -N--hydroxybutyryllysine (Kbhb) and -N-lactyllysine (Kla), that each comprise a pair of mirror image stereoisomers. Both modifications are found on histones, where they affect gene transcription in response to specific metabolic states, and they are found on cytosolic and mitochondrial enzymes involved in fatty acid oxidation (Kbhb) and glycolysis (Kla), respectively. Thus, chiral modifications to lysine side chains give rise to two distinct diastereomeric products, with separate metabolic origins and potentially different activities exhibited by writer and eraser enzymes. Lysine L-lactylation derives from L-lactate, a major energy carrier produced from pyruvate after glycolysis, and it is highly induced by metabolic states such as the Warburg effect. L-Lactate can possibly be activated by acyl-coenzyme A (CoA) synthetases and transferred to lysine residues by histone acetyltransferases such as p300. D-Lactylation, on the other hand, arises primarily from a non-enzymatic reaction with D-lactylglutathione, an intermediate in the glyoxalase pathway. In addition to their distinct origin, we found that both K(L-la) and K(D-la) modifications are erased by HDACs with different catalytic efficiencies. Also, K(L-bhb) and K(D-bhb) arise from different metabolites but depend on interconnected metabolic pathways, while the two stereoisomers of -N-3-hydroxy-3-methylglutaryllysine (Khmg) derive from a single precursor that may then be regulated differently by eraser enzymes. Distinguishing between the individual stereoisomers of PTMs is therefore of crucial importance. In the present Account, we will (1) revisit the long-standing evidence for distinct production and dynamics of enantiomeric forms of chiral metabolites that serve as epsilon-N-acyllysine PTMs and (2) highlight the outstanding questions that arise from the recent literature on chiral lysine PTMs resulting from these metabolites.

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Section: D-b-hydroxybutyrylationmentioning

confidence: 99%

Chiral Posttranslational Modification to Lysine epsilon-Amino Groups

Moreno–Yruela

Bæk

Monda

et al. 2022

Preprint

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“…Comparative analyses between unmodified and acetylated structures of AHCY indicate a local hydrogen-bound alteration in the vicinity of the modified lysine residues, indicating that slight structural changes in AHCY might have a significant functional impact on its catalytic activity. Two additional modifications, based on the conjugation with short fatty acid derivatives on lysine residues, have recently been reported: the 2-hydroxyisobutyrylation (hib) of lysine (K) 186, and the β-hydroxybutyrylation (bhb) of several lysines (20, 43, 188, 204, 389, and 405) (Huang et al, 2018;Koronowski et al, 2021). In particular, forced K-bhb inhibits AHCY activity in mouse embryonic fibroblast (MEFs) and mouse liver (Koronowski et al, 2021).…”

Section: Enzymatic Activity Regulationmentioning

confidence: 99%

“…Two additional modifications, based on the conjugation with short fatty acid derivatives on lysine residues, have recently been reported: the 2-hydroxyisobutyrylation (hib) of lysine (K) 186, and the β-hydroxybutyrylation (bhb) of several lysines (20, 43, 188, 204, 389, and 405) (Huang et al, 2018;Koronowski et al, 2021). In particular, forced K-bhb inhibits AHCY activity in mouse embryonic fibroblast (MEFs) and mouse liver (Koronowski et al, 2021). Enzymatic assays from cells ectopically expressing mutants show that K188R, K389R, and K405R substitutions compromise AHCY activity (Koronowski et al, 2021).…”

Section: Enzymatic Activity Regulationmentioning

confidence: 99%

“…In particular, forced K-bhb inhibits AHCY activity in mouse embryonic fibroblast (MEFs) and mouse liver (Koronowski et al, 2021). Enzymatic assays from cells ectopically expressing mutants show that K188R, K389R, and K405R substitutions compromise AHCY activity (Koronowski et al, 2021). In addition to lysine modification, mouse AHCY is posttranslationally modified with an O-linked β-N-acetylglucosamine sugar (O-GlcNAcylation) at threonine 136 (Zhu et al, 2020).…”

Section: Enzymatic Activity Regulationmentioning

confidence: 99%

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Functional and Pathological Roles of AHCY

Vizán

Croce

Aranda

2021

Front. Cell Dev. Biol.

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Adenosylhomocysteinase (AHCY) is a unique enzyme and one of the most conserved proteins in living organisms. AHCY catalyzes the reversible break of S-adenosylhomocysteine (SAH), the by-product and a potent inhibitor of methyltransferases activity. In mammals, AHCY is the only enzyme capable of performing this reaction. Controlled subcellular localization of AHCY is believed to facilitate local transmethylation reactions, by removing excess of SAH. Accordingly, AHCY is recruited to chromatin during replication and active transcription, correlating with increasing demands for DNA, RNA, and histone methylation. AHCY deletion is embryonic lethal in many organisms (from plants to mammals). In humans, AHCY deficiency is associated with an incurable rare recessive disorder in methionine metabolism. In this review, we focus on the AHCY protein from an evolutionary, biochemical, and functional point of view, and we discuss the most recent, relevant, and controversial contributions to the study of this enzyme.

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“…However, having real objectives can help you maintain a fitness program in the long term[51]. Simply it is important to warm up before you start your walking exercise like arm swings, leg kicks, and walking lunges doing so can help prevent injuries and improve your flexibility and reduce soreness[52]. Alternatively, walking exercise training in the older community groups warm up by doing easy movements of the walking exercise training you're planning to do.…”

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confidence: 99%

Combined Ketogenic Diet and Walking Exercise Interventions in Community Older Groups

Wu¹

2021

Preprint

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The ketogenic diet and walking exercise training activity are two key public health lifestyle factors. The potential of combined lifestyle factors interventions focused on getting to compliance in forced exercise. A balanced ketogenic diet and regular exercise activity is a key modifiable factor to the prevention and management of chronic diseases. Influence health across the lifespan and reduction of the risk of premature death through several biological mechanisms. Community older group’s lifestyle factors interventions contribute identity in their natural living environment. While the older health benefits of walking exercise training strategies are commonly to study, combined ketogenic diet and walking exercise interventions have induced greater benefits in community older groups.

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Ketogenesis Impact on Liver Metabolism Revealed by Proteomics of Lysine β-hydroxybutyrylation

Cited by 12 publications

References 67 publications

Chiral Posttranslational Modification to Lysine epsilon-Amino Groups

Chiral Posttranslational Modification to Lysine epsilon-Amino Groups

Functional and Pathological Roles of AHCY

Combined Ketogenic Diet and Walking Exercise Interventions in Community Older Groups

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