Chemical and structural biology of protein lysine deacetylases

Yoshida, Minoru; Kudo, Norio; Kosono, Saori; Ito, Akihiro

doi:10.2183/pjab.93.019

Cited by 77 publications

(53 citation statements)

References 183 publications

(200 reference statements)

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“…Since protein acylation is regulated by metabolites, such as acyl-CoA and NAD + , this modification could play a role in the regulation of protein function in response to nutrient signals and/or metabolism. [1][2][3][4] Corynebacterium glutamicum is an excellent glutamate producer that is utilized for industrial production of amino acids including L-glutamate and L-lysine. 5) We reported that the acetylation and succinylation profiles of many enzymes are drastically changed in response to L-glutamate overproduction in C. glutamicum, including enzymes involved in central metabolic pathways.…”

mentioning

confidence: 99%

Effect of lysine succinylation on the regulation of 2-oxoglutarate dehydrogenase inhibitor, OdhI, involved in glutamate production inCorynebacterium glutamicum

Komine‐Abe

Nagano‐Shoji

Kubo

et al. 2017

Bioscience, Biotechnology, and Biochemistry

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In Corynebacterium glutamicum, the activity of the 2-oxoglutarate dehydrogenase (ODH) complex is negatively regulated by the unphosphorylated form of OdhI protein, which is critical for L-glutamate overproduction. We examined the potential impact of protein acylation at lysine (K)-132 of OdhI in C. glutamicum ATCC13032. The K132E succinylation-mimic mutation reduced the ability of OdhI to bind OdhA, the catalytic subunit of the ODH complex, which reduced the inhibition of ODH activity. In vitro succinylation of OdhI protein also reduced the ability to inhibit ODH, and the K132R mutation blocked the effect. These results suggest that succinylation at K132 may attenuate the OdhI function. Consistent with these results, the C. glutamicum mutant strain with OdhI-K132E showed decreased L-glutamate production. Our results indicated that not only phosphorylation but also succinylation of OdhI protein may regulate L-glutamate production in C. glutamicum.

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mentioning

confidence: 99%

Effect of lysine succinylation on the regulation of 2-oxoglutarate dehydrogenase inhibitor, OdhI, involved in glutamate production inCorynebacterium glutamicum

Komine‐Abe

Nagano‐Shoji

Kubo

et al. 2017

Bioscience, Biotechnology, and Biochemistry

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“…The first HDAC6 inhibitor to be investigated was the natural compound trichostatin (TSA) [ 323 , 324 ]. It is a non selective HDAC inhibitor that acts by binding to the zinc ion at the HDAC active site of most zinc-dependent HDACs, including HDAC6 [ 325 ]. Its in vitro supplementation has been reported to lead to the hyperacetylation of tubulin in mammalian cells [ 324 ].…”

Section: Microtubule-targeting Agentsmentioning

confidence: 99%

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

Sferra

Nicita

Bertini

2020

IJMS

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Neurons are particularly susceptible to microtubule (MT) defects and deregulation of the MT cytoskeleton is considered to be a common insult during the pathogenesis of neurodegenerative disorders. Evidence that dysfunctions in the MT system have a direct role in neurodegeneration comes from findings that several forms of neurodegenerative diseases are associated with changes in genes encoding tubulins, the structural units of MTs, MT-associated proteins (MAPs), or additional factors such as MT modifying enzymes which modulating tubulin post-translational modifications (PTMs) regulate MT functions and dynamics. Efforts to use MT-targeting therapeutic agents for the treatment of neurodegenerative diseases are underway. Many of these agents have provided several benefits when tested on both in vitro and in vivo neurodegenerative model systems. Currently, the most frequently addressed therapeutic interventions include drugs that modulate MT stability or that target tubulin PTMs, such as tubulin acetylation. The purpose of this review is to provide an update on the relevance of MT dysfunctions to the process of neurodegeneration and briefly discuss advances in the use of MT-targeting drugs for the treatment of neurodegenerative disorders.

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“…Here, we focus on the second family, which consists of 11 metal‐dependent KDACs in human cells. These enzymes all share a highly conserved catalytic domain (Figure 2) and utilize a divalent transition metal cation in the active site to promote hydrolysis, resulting in the removal of the acetate from lysine side chains 9,14,15 . The identity of the transition metal is usually Zn 2+ in vitro, but evidence exists that some KDACs may utilize Fe 2+ in vivo 14,16 .…”

Section: Lysine Deacetylasesmentioning

confidence: 99%

Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

Toro

Watt

2020

FASEB j.

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Lysine acetylation is a posttranslational modification that occurs on thousands of human proteins, most of which are cytoplasmic. Acetylated proteins are involved in numerous cellular processes and human diseases. Therefore, how the acetylation/deacetylation cycle is regulated is an important question. Eleven metal‐dependent lysine deacetylases (KDACs) have been identified in human cells. These enzymes, along with the sirtuins, are collectively responsible for reversing lysine acetylation. Despite several large‐scale studies which have characterized the acetylome, relatively few of the specific acetylated residues have been matched to a proposed KDAC for deacetylation. To understand the function of lysine acetylation, and its association with diseases, specific KDAC‐substrate pairs must be identified. Identifying specific substrates of a KDAC is complicated both by the complexity of assaying relevant activity and by the non‐catalytic interactions of KDACs with cellular proteins. Here, we discuss in vitro and cell‐based experimental strategies used to identify KDAC‐substrate pairs and evaluate each for the purpose of directly identifying non‐histone substrates of metal‐dependent KDACs. We propose criteria for a combination of reproducible experimental approaches that are necessary to establish a direct enzymatic relationship. This critical analysis of the literature identifies 108 proposed non‐histone substrate‐KDAC pairs for which direct experimental evidence has been reported. Of these, five pairs can be considered well‐established, while another thirteen pairs have both cell‐based and in vitro evidence but lack independent replication and/or sufficient cell‐based evidence. We present a path forward for evaluating the remaining substrate leads and reliably identifying novel KDAC substrates.

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Chemical and structural biology of protein lysine deacetylases

Cited by 77 publications

References 183 publications

Effect of lysine succinylation on the regulation of 2-oxoglutarate dehydrogenase inhibitor, OdhI, involved in glutamate production inCorynebacterium glutamicum

Effect of lysine succinylation on the regulation of 2-oxoglutarate dehydrogenase inhibitor, OdhI, involved in glutamate production inCorynebacterium glutamicum

Microtubule Dysfunction: A Common Feature of Neurodegenerative Diseases

Critical review of non‐histone human substrates of metal‐dependent lysine deacetylases

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