Dehomocysteinylation is catalysed by the sirtuin‐2‐like bacterial lysine deacetylase CobB

Mei, Xinyu; He, Xinlei; Huang, Lei; Qi, Dashi; Nie, Ji; Li, Yang; Wen, Shi Wu; Zhao, Shimin

doi:10.1111/febs.13912

Cited by 8 publications

(8 citation statements)

References 47 publications

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“…In addition to proteolytic turnover, N-Hcy residues can be removed from N-Hcy-protein by a dehomocysteinylation reaction, analogous to the deacetylation of protein Lys res-idues. A recent study shows that Cob-2, a Sir2-like bacterial Lys deacetylase, catalyzes dehomocysteinylation of N-Hcyprotein both in vitro and in vivo in the bacterium Salmonella enterica (212). Measurements of catalytic efficiencies with N-Hcy-Lys-peptide, N-acetyl-Lys-peptide, and Nsuccinyl-Lys-peptide as substrates indicate that the Cob-2 enzyme does not discriminate between these substrates and acts as a general N-acyl-Lys-peptide deacylase.…”

Section: Dehomocysteinylationmentioning

confidence: 99%

Homocysteine Modification in Protein Structure/Function and Human Disease

Jakubowski

2019

Physiological Reviews

223

219

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Epidemiological studies established that elevated homocysteine, an important intermediate in folate, vitamin B12, and one carbon metabolism, is associated with poor health, including heart and brain diseases. Earlier studies show that patients with severe hyperhomocysteinemia, first identified in the 1960s, exhibit neurological and cardiovascular abnormalities and premature death due to vascular complications. Although homocysteine is considered to be a nonprotein amino acid, studies over the past 2 decades have led to discoveries of protein-related homocysteine metabolism and mechanisms by which homocysteine can become a component of proteins. Homocysteine-containing proteins lose their biological function and acquire cytotoxic, proinflammatory, proatherothrombotic, and proneuropathic properties, which can account for the various disease phenotypes associated with hyperhomocysteinemia. This review describes mechanisms by which hyperhomocysteinemia affects cellular proteostasis, provides a comprehensive account of the biological chemistry of homocysteine-containing proteins, and discusses pathophysiological consequences and clinical implications of their formation.

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Section: Dehomocysteinylationmentioning

confidence: 99%

Homocysteine Modification in Protein Structure/Function and Human Disease

Jakubowski

2019

Physiological Reviews

223

219

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“…Perhaps the selectivity of CobB for certain substrates allows for greater promiscuity for removing various modifications. Indeed, CobB may be a deacylase capable of removing, in addition to acetyl groups, succinyl (143), propionyl (144, 145), lipoyl (146), and homocysteine (147) functional groups.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms, Detection, and Relevance of Protein Acetylation in Prokaryotes

Christensen

Baumgartner

Xie

et al. 2019

mBio

116

101

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Posttranslational modification of a protein, either alone or in combination with other modifications, can control properties of that protein, such as enzymatic activity, localization, stability, or interactions with other molecules. N-ε-Lysine acetylation is one such modification that has gained attention in recent years, with a prevalence and significance that rival those of phosphorylation. This review will discuss the current state of the field in bacteria and some of the work in archaea, focusing on both mechanisms of N-ε-lysine acetylation and methods to identify, quantify, and characterize specific acetyllysines. Bacterial N-ε-lysine acetylation depends on both enzymatic and nonenzymatic mechanisms of acetylation, and recent work has shed light into the regulation of both mechanisms. Technological advances in mass spectrometry have allowed researchers to gain insight with greater biological context by both (i) analyzing samples either with stable isotope labeling workflows or using label-free protocols and (ii) determining the true extent of acetylation on a protein population through stoichiometry measurements. Identification of acetylated lysines through these methods has led to studies that probe the biological significance of acetylation. General and diverse approaches used to determine the effect of acetylation on a specific lysine will be covered.

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“…For E. coli, CobB was shown to affect the ac(et)ylation state of thousands of proteins and deletion of cobB resulted in upregulation of 10% of all acetylation sites in E. coli under the conditions of the study (Weinert et al, 2013a). Moreover, CobB removes diverse acyl-groups from lysine side chains suggesting to play a similar role as detoxifying enzyme suppressing low stoichiometry ac(et)ylation that might occur due to non-enzymatic ac(et)ylation by accumulation of ac(et)yl-CoA and acetyl-phosphate (Peng et al, 2011;AbouElfetouh et al, 2015;Mei et al, 2016;Weinert et al, 2017;Dong et al, 2019;Wei et al, 2019). Furthermore, it was shown that CobB does neither show preference nor discriminate between enzymatic and non-enzymatic acetylation sites (AbouElfetouh et al, 2015).…”

Section: Acetylphosphate-the Major Driver For Non-enzymatic Ac(et)ylation In Bacteriamentioning

confidence: 87%

“…Recently, CobB was shown be an efficient lipoamidase in analogy to mammalian SIRT4 acting on important lipoylated metabolic complexes, such as the α-ketoglutarate dehydrogenase (KDH) complex, the pyruvate dehydrogenase (PDH) complex and the glycine cleavage (GCV) complex and as de-2hydroxyisobutyrylase modulating enolase activity (Rowland et al, 2017;Dong et al, 2019). Furthermore, CobB was shown to act as de-homocysteinylase and it is supposed to revert protein lysine propionylation (Mei et al, 2016;Sun et al, 2016). SirTMs do not possess any deacylase activity, which is most likely due to the absence of the catalytic histidine residue (Rack et al, 2015;Olesen et al, 2018).…”

Section: Substrate Preference Of Bacterial Sirtuinsmentioning

confidence: 99%

Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

Lammers

2021

Front. Microbiol.

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Ac(et)ylation is a post-translational modification present in all domains of life. First identified in mammals in histones to regulate RNA synthesis, today it is known that is regulates fundamental cellular processes also in bacteria: transcription, translation, metabolism, cell motility. Ac(et)ylation can occur at the ε-amino group of lysine side chains or at the α-amino group of a protein. Furthermore small molecules such as polyamines and antibiotics can be acetylated and deacetylated enzymatically at amino groups. While much research focused on N-(ε)-ac(et)ylation of lysine side chains, much less is known about the occurrence, the regulation and the physiological roles on N-(α)-ac(et)ylation of protein amino termini in bacteria. Lysine ac(et)ylation was shown to affect protein function by various mechanisms ranging from quenching of the positive charge, increasing the lysine side chains’ size affecting the protein surface complementarity, increasing the hydrophobicity and by interfering with other post-translational modifications. While N-(ε)-lysine ac(et)ylation was shown to be reversible, dynamically regulated by lysine acetyltransferases and lysine deacetylases, for N-(α)-ac(et)ylation only N-terminal acetyltransferases were identified and so far no deacetylases were discovered neither in bacteria nor in mammals. To this end, N-terminal ac(et)ylation is regarded as being irreversible. Besides enzymatic ac(et)ylation, recent data showed that ac(et)ylation of lysine side chains and of the proteins N-termini can also occur non-enzymatically by the high-energy molecules acetyl-coenzyme A and acetyl-phosphate. Acetyl-phosphate is supposed to be the key molecule that drives non-enzymatic ac(et)ylation in bacteria. Non-enzymatic ac(et)ylation can occur site-specifically with both, the protein primary sequence and the three dimensional structure affecting its efficiency. Ac(et)ylation is tightly controlled by the cellular metabolic state as acetyltransferases use ac(et)yl-CoA as donor molecule for the ac(et)ylation and sirtuin deacetylases use NAD+ as co-substrate for the deac(et)ylation. Moreover, the accumulation of ac(et)yl-CoA and acetyl-phosphate is dependent on the cellular metabolic state. This constitutes a feedback control mechanism as activities of many metabolic enzymes were shown to be regulated by lysine ac(et)ylation. Our knowledge on lysine ac(et)ylation significantly increased in the last decade predominantly due to the huge methodological advances that were made in fields such as mass-spectrometry, structural biology and synthetic biology. This also includes the identification of additional acylations occurring on lysine side chains with supposedly different regulatory potential. This review highlights recent advances in the research field. Our knowledge on enzymatic regulation of lysine ac(et)ylation will be summarized with a special focus on structural and mechanistic characterization of the enzymes, the mechanisms underlying non-enzymatic/chemical ac(et)ylation are explained, recent technological progress in the field are presented and selected examples highlighting the important physiological roles of lysine ac(et)ylation are summarized.

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Dehomocysteinylation is catalysed by the sirtuin‐2‐like bacterial lysine deacetylase CobB

Cited by 8 publications

References 47 publications

Homocysteine Modification in Protein Structure/Function and Human Disease

Homocysteine Modification in Protein Structure/Function and Human Disease

Mechanisms, Detection, and Relevance of Protein Acetylation in Prokaryotes

Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

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