ArticleBiochemistry2010
Kinetic mechanism of the Rtt109-Vps75 histone acetyltransferase-chaperone complex.
Article in Biochemistry, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 35 citations in OpenAlex.
- Catalysis by protein acetyltransferase Gcn5.Biochimica et biophysica acta. Gene regulatory mechanisms · 2021Review
- The evolving metabolic landscape of chromatin biology and epigenetics.Nature reviews. Genetics · 2020Review
- Stoichiometry of Rtt109 complexes with Vps75 and histones H3-H4.Life science alliance · 2020Article
- Enzymatic and nonenzymatic protein acetylations control glycolysis process in liver diseases.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Review
- Two factor authentication: Asf1 mediates crosstalk between H3 K14 and K56 acetylation.Nucleic acids research · 2019Article
- Multisite Substrate Recognition in Asf1-Dependent Acetylation of Histone H3 K56 by Rtt109.Cell · 2018Article
- Structural and Functional Role of Acetyltransferase hMOF K274 Autoacetylation.The Journal of biological chemistry · 2016Article
- Molecular Basis for Histone Acetyltransferase Regulation by Binding Partners, Associated Domains, and Autoacetylation.ACS chemical biology · 2016Review
- Protein acetylation in metabolism - metabolites and cofactors.Nature reviews. Endocrinology · 2016Review
- PAINS in the assay: chemical mechanisms of assay interference and promiscuous enzymatic inhibition observed during a sulfhydryl-scavenging HTS.Journal of medicinal chemistry · 2015Article
- Article
- Protein acetylation and acetyl coenzyme a metabolism in budding yeast.Eukaryotic cell · 2014Review
- Writers and readers of histone acetylation: structure, mechanism, and inhibition.Cold Spring Harbor perspectives in biology · 2014Review
- A small molecule inhibitor of fungal histone acetyltransferase Rtt109.Bioorganic & medicinal chemistry letters · 2013Article
- Review
- A cell-free fluorometric high-throughput screen for inhibitors of Rtt109-catalyzed histone acetylation.PloS one · 2013Article
- Identification and characterization of small molecule inhibitors of a plant homeodomain finger.Biochemistry · 2012Article
- Human protein N-terminal acetyltransferase hNaa50p (hNAT5/hSAN) follows ordered sequential catalytic mechanism: combined kinetic and NMR study.The Journal of biological chemistry · 2012Article
- Chromatin-mediated Candida albicans virulence.Biochimica et biophysica acta · 2012Article
- Article
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Rtt109 is a histone acetyltransferase (HAT) involved in promoting genomic stability, DNA repair, and transcriptional regulation. Rtt109 associates with the NAP1 family histone chaperone Vps75 and stimulates histone acetylation. Here we explore the mechanism of histone acetylation and report a detailed kinetic investigation of the Rtt109-Vps75 complex. Rtt109 and Vps75 form a stable complex with nanomolar binding affinity (K(d) = 10 +/- 2 nM). Steady-state kinetic analysis reveals evidence of a sequential kinetic mechanism whereby the Rtt109-Vps75 complex, AcCoA, and histone H3 substrates form a complex prior to chemical catalysis. Product inhibition studies demonstrate that CoA binds competitively with AcCoA, and equilibrium measurements reveal AcCoA or CoA binding is not stimulated in the presence of H3 substrate. Additionally, the Rtt109-Vps75 complex binds H3 substrates in the absence AcCoA. Pre-steady-state kinetic analysis suggests the chemical attack of substrate lysine on the bound AcCoA is the rate-limiting step of catalysis, while the pH profile of k(cat) reveals a critical ionization with a pK(a) of 8.5 that must be unprotonated for catalysis. Amino acid substitution at D287 and D288 did not substantially change the shape of the k(cat)-pH profile, suggesting these conserved residues do not function as base catalysts for histone acetylation. However, the D288N mutant revealed a dramatic 1000-fold decrease in k(cat)/K(m) for AcCoA, consistent with a role in AcCoA binding. Together, these data support a sequential mechanism in which AcCoA and H3 bind to the Rtt109-Vps75 complex without obligate order, followed by the direct attack of the unprotonated epsilon-amino group on AcCoA, transferring the acetyl group to H3 lysine residues.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.