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Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases
Open accessAbstract
Previous findings have suggested that class IIa histone deacetylases (HDACs) (HDAC4, -5, -7, and -9) are inactive on acetylated substrates, thus differing from class I and IIb enzymes. Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates. We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs. Moreover, an HDAC4 catalytic domain purified from bacteria was 1,000-fold less active than class I HDACs on standard substrates. A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His. Given the high structural conservation of HDAC active sites, we predicted the class IIa His-Nε2 to be too far away to functionally substitute the class I Tyr-OH in catalysis. Consistently, a Tyr-to-His mutation in class I HDACs severely reduced their activity. More importantly, a His-976-Tyr mutation in HDAC4 produced an enzyme with a catalytic efficiency 1,000-fold higher than WT, and this “gain of function phenotype” could be extended to HDAC5 and -7. We also identified trifluoroacetyl-lysine as a class IIa-specific substrate in vitro . Hence, vertebrate class IIa HDACs may have evolved to maintain low basal activities on acetyl-lysines and to efficiently process restricted sets of specific, still undiscovered natural substrates.
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TL;DR
Vertebrate class IIa HDACs carry a conserved active-site Tyr-to-His substitution that makes them very inefficient on canonical acetyl-lysine substrates, with most deacetylase activity in class IIa complexes coming from associated class I HDACs. A single His-to-Tyr mutation restores high catalytic activity, and trifluoroacetyl-lysine is identified as a class IIa-specific substrate in vitro.
Key findings
- The catalytic Tyr conserved in other HDACs is replaced by His in vertebrate class IIa HDACs; mutating HDAC3 Y298 to H abolished activity on pepH4-AcK16, and HDAC1 Y303H reduced activity 5- to 8-fold.
- HDAC4 catalytic domain purified from E. coli had measurable activity but was at least 1,000-fold lower than class I HDACs and 100-fold lower than the HDAC4-FLAG complex; it was inactive on pepH4-AcK16.
- HDAC4 H976Y produced a gain-of-function phenotype: >20-fold increased activity for HDAC4-FLAG and >1,000-fold for HDAC4-CD, reaching levels comparable to class I enzymes; similar effects were seen for HDAC5 H1006Y and HDAC7 H843Y.
- Trifluoroacetyl-lysine was identified as a class IIa-specific substrate in vitro, processed by HDAC4 full-length and catalytic domain and by three class IIa enzymes, but poorly by class I and class IIb HDACs.
Methods
- HDAC4 was used as a representative class IIa model with four approaches: HDAC inhibitor binding/inhibition comparison, functional analysis of purified HDAC4 catalytic domain expressed in E. coli, structure-guided mutagenesis, and substrate screening.
- Deacetylase assays used 3[H]acetyl-core histones purified from HeLa cells or fluorescent pepH4-AcK16, plus a commercial Fluor de Lys assay; HDAC inhibitor activities were measured by preincubation with enzymes before substrate addition.
- Binding was assessed by pull-down with biotinylated LAQ824/apicidin derivatives and by UV cross-linking; sequence analysis used CLUSTALW/Genedoc and structural analysis used bacterial class II homolog PDB 1ZZ1.
Limitations
- Stated: the lack of isotype/class-specific HDAC inhibitors limits distinguishing class IIa intrinsic activity from associated class I HDACs; attempts to obtain active recombinant class IIa HDACs in heterologous systems were unsuccessful, and it remains unknown whether this reflects missing cofactors or endogenous class I enzymes.
- Stated: the precise role of HDAC4 catalytic activity in atypical biological contexts remains to be elucidated, and identification of additional biological activities/substrates dependent on class IIa H-associated activity requires further work.
- Evident from the text: the study relies heavily on in vitro assays and ectopically expressed proteins, and no natural physiological class IIa-specific substrate is identified; the proposed specialized vertebrate class IIa activity is therefore inferred from synthetic substrate data.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, we have identified trif luoroacetyl-lysine as a class IIa-specific substrate in vitro.”
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In the paper
“However, the Y298H substitution in HDAC3 did not affect its association with N-CoR DAD (Fig. 2B), suggesting that the integrity of the catalytic domain was preserved.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
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In the paper
“Furthermore, replacement of Y with H produced a loss-of-function phenotype as severe as that caused by replacement with F (SI Fig. 8A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As predicted, replacing the active site Y with H was sufficient to abolish the enzymatic activity on a histone H4-derived peptide containing a single acetyl-lysine (pepH4-AcK16) (Fig. 2A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
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In the paper
“As shown in SI Fig. 8C, the mutation actually reduced HDAC1 deacetylase activity 5-to 8-fold.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC Substrates.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Class IIa HDACs possess a weak but measurable intrinsic capability of hydrolyzing acetyl-lysines in vitro.”
- Also stated in: § HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs. · plain
“HDAC4-CD showed a measurable deacetylase activity both in the histone-based (Fig. 4B) and the commercial (SI Fig. 10A) HDAC assays.”
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs. · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Indeed, catalytic activity toward canonical HDAC substrates could be restored by a single H-to-Y substitution in the active site.”
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In the paper
“As shown in SI Fig. 8E, mutation into F did not alter the activity of the purified HDAC4 complex on pepH4-AcK16.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Class IIa HDACs with the H Mutated into F Are Not Impaired in Their
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In the paper
“The H976Y mutation did not enhance HDAC4 transcriptional inhibitory activity, despite its clear effect on the enzymatic activity in vitro (SI Fig. 12 A).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
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In the paper
“When challenged in activity assays, HDAC4-CD showed a measurable deacetylase activity both in the histone-based (Fig. 4B) and the commercial (SI Fig. 10A) HDAC assays.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
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- It may state two separate claims as one. 23
- The quote only partly states this claim. 1
- Probably not a substantial claim. 4
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the vertebrate class IIa HDACs, the catalytic Y is replaced by an H, a conservative substitution, whereas other functional residues are virtually always conserved (SI Fig. 7).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Sequence and Structure Analysis Indicates that Vertebrate Class IIa
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In the paper
“This protein was efficiently pulled-down on biotinylated LAQ824 beads (Fig. 4A), suggesting that the structural integrity of the catalytic domain was preserved in the recombinant truncated mutant.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, LAQ824 and apicidin had similar effects in this assay in contrast to the different inhibitory potencies and binding affinities shown in vitro.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Again Y mutants exhibited strongly increased activity compared with WT and, like the HDAC4 mutant, could be inhibited by LAQ824 but were resistant to apicidin.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
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In the paper
“Pull-down was significantly reduced by preincubation with an excess of free LAQ824, whereas apicidin and MS275 did not show competition, thus confirming and directly validating the results obtained with ectopic HDAC4-FLAG.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Different than WT HDAC4-FLAG, Y mutants were sensitive only to the inhibitory effect of LAQ824, but they were highly resistant to inhibition by compounds belonging to different chemical classes (MS-275, apicidin, and its open derivative), all of which are active on class I HDACs (data not shown).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In addition, HDAC4-CD was completely inactive on pepH4-AcK16 and on a number of acetylated peptides grafted from nonhistonic HDAC substrates (data not shown).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Having ascertained that class IIa HDACs are not proficient enzymes on acetyl-lysines, we sought alternative in vitro substrates.”
- Also stated in: § HDAC4 Compound Binding Assays. · boosted
“Here, we present evidence supporting this view and demonstrate that class IIa HDACs are very inefficient enzymes on standard substrates.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Identification of a Class IIa-Specific Substrate.
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § HDAC4 Compound Binding Assays. · boosted
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, this compound was actively and specifically processed by three different class IIa enzymes, whereas it was a poor substrate for both class I and class IIb HDACs (Fig. 6).”
- Also stated in: § Discussion · plain
“We have identified a class IIa-specific synthetic substrate, trifluoroacetyl-lysine.”
- Also stated in: § HDAC4 Compound Binding Assays. · plain
“Trifluoroacetyl-lysine is a class IIa-specific substrate in vitro.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Identification of a Class IIa-Specific Substrate.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We identified HDAC inhibitors unable to bind recombinant human HDAC4 while showing inhibition in a typical HDAC4 enzymatic assay, suggesting that the observed activity rather reflects the involvement of endogenous copurified class I HDACs.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Compound Binding Assays.
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Interestingly, ascidian class IIa sequences also lack one of the conserved Zn ligands, a D is replaced by an S (SI Fig. 7).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In class IIa HDACs, three different residues (Y, H, and F) are observed at this position and, given the particular structural context, it is unlikely that for each residue a concomitant conformational change would occur.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Sequence and Structure Analysis Indicates that Vertebrate Class IIa
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This experimental evidence also proved the HDAC4 catalytic domain to be properly folded under our experimental conditions, because a single amino acid substitution was sufficient to confer high enzymatic activity.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, the HDAC4-CD mutant showed an inhibition profile identical to that of the full-length HDAC4-FLAG mutant, suggesting that the observed selectivity is directly related to the catalytic domain and does not depend on additional N-terminal regions.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Together, these results demonstrate that HDAC4 intrinsic catalytic activity is low on canonical acetylated substrates and does not contribute significantly to the overall activity observed in purified ectopic HDAC4 complexes.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4 Exhibits Weak Enzymatic Activity on Canonical HDAC Substrates in the Absence of Associated Endogenous Class I HDACs.
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“All class IIa members expressed in mammalian cells are known to recruit class I HDACs, which possess high deacetylase activities both in vitro and in cells (18)(19)(20).”
What the sources say
- Not checked yetcites (18)(19)(20)
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, compounds that did not inhibit the H976Ysubstituted enzymes were those that did not bind WT HDAC4, thus implying that the mutant proteins retain the WT selectivity of interactions.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > An HDAC4 H976Y Mutation Restores Canonical Deacetylase Activity.
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In the paper
“It is well documented that class IIa HDACs are potent and selective transcriptional repressors (4).”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > HDAC4-Mediated Transcriptional Repression Does Not Depend on Its
What the sources say
- Not checked yetcites [4] source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“This finding was confirmed both in the isolated catalytic domain expressed in a prokaryotic system as well as for the full-length enzymes expressed in mammalian cells, including HDAC5 and -7.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The emergent theme predicts class IIa HDACs with intrinsically different catalytic activities for the two groups: (i) canonical HDAC activity in invertebrates and (ii) a more specialized enzymatic activity in vertebrates.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Mechanistically, the presence of the trifluoro group should destabilize the amide bond and thus favor the reaction even in the absence of transition-state stabilization, as postulated for the His-containing class IIa HDACs.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- The authors state this as an assumption: The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mean values of at least two independent assays are reported.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Methods Sequence Analysis and Modeling.
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our MEF2 reporter gene data are in agreement with these findings, excluding HDAC4 catalytic activity for being responsible for transcriptional repression and pointing to the involvement of class I enzymes that are equally sensitive to the inhibition by both LAQ824 and apicidin.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Finally, our data also imply that class IIa HDACs should be considered a distinct class of therapeutic targets, concerning both their natural substrates and selective mechanisms of inhibition.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Load-bearingStrength:hedged· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
- Rests on an assumption: Vertebrate class IIa HDACs have natural substrates that are not canonical acetyl-lysines.
- Rests on an assumption: In vitro substrate specificity of class IIa HDACs reflects their in vivo biological function.
None of the sources cited for this claim have been checked yet.
In the paper
“More recently, it has been shown that both Sirt1 (28) and HDAC3 (29), and not HDAC4 or -5, efficiently deacetylate MEF2D, thus contributing to MEF2Ddependent transcriptional repression.”
§ Unraveling the hidden catalytic activity of vertebrate class IIa histone deacetylases > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The authors state this as an assumption.
The catalytic mechanism of HDACs is conserved across the enzymes and species considered.
“Based on our results, the presence of an F should be incompatible with activity, provided that the catalytic mechanism is conserved.”
The paper relies on this without support.
Vertebrate class IIa HDACs have natural substrates that are not canonical acetyl-lysines.
“Future work will undoubtedly identify these yet unknown physiological substrates and further reveal the already complex biological activities of these enzymes.”
The paper relies on this without support.
In vitro substrate specificity of class IIa HDACs reflects their in vivo biological function.
“our results point to a previously unknown, specific catalytic activity of vertebrate class IIa HDACs.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Class IIa enzymes (Lahm et al., 2007) as well as HDAC3 (Madsen and Olsen, 2012a), HDAC8 (Bradner et al., 2010), and HDAC11 (Inks et al., 2012) removed the physiologically non-relevant trifluoroacetamide (Ktfa).”
From Histone deacetylase 11 is an ε-N-Myristoyllysine hydrolase (2018) · cites this paper as Lahm et al., 2007
In the citing paper
“In vertebrates, this subfamily is characterized by limited catalytic activity, mainly due to the replacement of a tyrosine (Y) with a histidine (H) residue in the enzymatic pocket (Lahm et al., 2007).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Lahm et al., 2007
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Claim of universal Tyr conservation overlooks ascidian class IIa homologs
MinorThe first statement says Tyr is conserved in every HDAC outside vertebrate class IIa enzymes. The paper later identifies ascidian class IIa homologs with Phe at that position; ascidians are not vertebrates.
“A catalytic Tyr is conserved in all HDACs except for vertebrate class IIa enzymes where it is replaced by His.”
“Yet another residue, F, is instead found in class IIa homologs of the ascidians Ciona intestinalis, Ciona savignyi, and Halocynthia roretzi.”
Citations
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Class II Histone Deacetylases Act as Signal-Responsive Repressors of Cardiac Hypertrophy
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Histone Deacetylase 4 Controls Chondrocyte Hypertrophy during Skeletogenesis
Vega, R. B., Matsuda, K., Oh, J., Barbosa, A. C. C., Yang, X., Meadows, E., McAnally, J., Pomajzl, C., Shelton, J. M., Richardson, J. A., et al. (2004) · Cell · doi:10.1016/j.cell.2004.10.024 · Cited by 805
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Items 501–600 of 609
Yang, B., Borgeaud, A. C., Aeschbach, L., & Dion, V. (2018) · ORCA Online Research @Cardiff (Cardiff University) · doi:10.1101/368480 · Cited by 1
Kelly, R., Stengel, K. R., Chandru, A., Johnson, L., Hiebert, S. W., & Cowley, S. M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.04.06.535398 · Cited by 1
Pham, L. (2012) · University of Minnesota Digital Conservancy (University of Minnesota)
Smooth Muscle Cell Differentiation from Embryonic Stem Cells: Role of HDAC7 and PDGF-BB
Sims, D., & Xiao, Q. (2011) · Springer eBooks · doi:10.1007/978-94-007-2828-8_7
An Overview of Epigenetic Mechanisms in Health and Disease
Westerland, C., & Karagiannis, T. C. (2014) · Springer eBooks · doi:10.1007/978-1-4939-0706-9_3
Identification of novel signaling pathways for cardiomyocyte differentiation and growth
Ye, J. (2012) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Elucidation of the Histone Deacetylase 6 Pharmacophore
Kalin, J. H. (2012) · Figshare
Mechanisms underlying the regulation and functions of HDAC7.
Gao, C. (2008) · OhioLink ETD Center (Ohio Library and Information Network)
Mechanisms underlying the neuroprotective effects of histone deacetylase inhibitors
Durham, B. S. (2015) · White Rose eTheses Online (University of Leeds, The University of Sheffield, University of York)
Erasers of Histone Acetylation: The Histone Deacetylase EnzymesPreprint
Seto, E., & Yoshida, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018713 · Cited by 2,105
The molecular pathogenesis of skeletal muscle atrophy
Bongers, K. S., Shibata, E. F., Snyder, P. M., Zabner, J., Moye-Rowley, S., Adams, C. M., & Henry, M. D. (2016) · doi:10.17077/etd.n2myp7k9
HDAC Signaling Networks in Heart Failure
Kronlage, M., Katus, H. A., & Backs, J. (2016) · Cardiac and vascular biology · doi:10.1007/978-3-319-41457-7_8
Epigenetic and Nongenomic Roles for Histone Deacetylases in Heart Failure
Blakeslee, W. W., Tatman, P. D., & McKinsey, T. A. (2016) · Cardiac and vascular biology · doi:10.1007/978-3-319-41457-7_9
Lewandowski, S. L. (2016) · eScholarship@UMassChan · doi:10.13028/m26p4d
Targeted Prodrugs of a Novel Platform Anthracycline: Doxazolidine
Rudnicki, D. L. (2012) · CU Scholar (University of Colorado Boulder)
Targeting proteostasis in atrial fibrillation
De-li, Z. (2015)
Structural, functional and inhibition studies of human histone deacetylase 7
Desravines, D. C. (2010) · HAL
Hydroxamic Acid-Containing Peptides in the Study of Histone Deacetylases
Moreno–Yruela, C., & Olsen, C. A. (2019) · Topics in medicinal chemistry · doi:10.1007/7355_2019_69
An investigation into Mef2-interacting proteins during embryonic muscle development of Drosophila
Cepraga, A. (2020) · ORCA Online Research @Cardiff (Cardiff University)
Association between Histone Deacetylase 9 Gene Polymorphism and Stroke in Chinese Han Population
Yang, X., Xu, H., Liu, D., Ma, R., Zhang, Y., & Wang, G. (2020) · Journal of Korean Neurosurgical Society · doi:10.3340/jkns.2020.0040
Schwartz, S., Wilson, S. J., Hale, T. K., & Fitzsimons, H. L. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.07.18.452850
Bothwell, M. A. (2020) · Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature · doi:10.3410/f.735708359.793577285
Ye, J., Zhong, S., Deng, Y., Yao, X., Liu, Q., Wang, J., & Xiao, S. (2022) · Research Square · doi:10.21203/rs.3.rs-1462010/v1
Sumoylated SnoN interacts with HDAC1 and p300/CBP to regulate EMT in mammary organoidsPreprint
Chanda, A., Sarkar, A., Deng, L., Bonni, A., & Bonni, S. (2022) · Research Square · doi:10.21203/rs.3.rs-2014830/v1
Cho, E. (2023) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2023-15419
Histone deacetylases and other epigenetic targets
Carta, F. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823974-2.00037-1
Pei, T., Zhang, M., Gao, Z., Lü, L., Bing, Z., Meng, J., Nwanade, C. F., Yuan, C., Yu, Z., & Liu, J. (2024) · Parasites & Vectors · doi:10.1186/s13071-024-06288-4
Genetically Encoded Fluorescent and Bioluminescent Probes for HDAC8
Wang, Y., Sun, L. N., & Xuan, W. (2025) · ChemBioChem · doi:10.1002/cbic.202500096
Vera, V. A., Childs, J. E., Kim, J., Matheos, D. P., & Wood, M. A. (2025) · eNeuro · doi:10.1523/eneuro.0590-24.2025
Thermal shift engagement assay for Class IIA histone deacetylase inhibitor screening
Kotsull, L. N., & Pflum, M. K. H. (2025) · Results in Chemistry · doi:10.1016/j.rechem.2025.102682
Li, Y., Zhou, C., Li, C., Qiao, J., Pang, Y., Luan, Y., & Gou, M. (2025) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2025.110938
Paluvai, H., Pepin, M. E., Schreiter, F. C., Saadatmand, A., Hagenmueller, M., & Backs, J. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.14.682279
Pantazis, J. C., & Palmer, A. C. (2025) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-25-0941
Tan, W. J., Hawley, H. R., Wilson, S. J., & Fitzsimons, H. L. (2024) · Figshare · doi:10.6084/m9.figshare.26659279
Tan, W. J., Hawley, H. R., Wilson, S. J., & Fitzsimons, H. L. (2024) · Figshare · doi:10.6084/m9.figshare.26659276
Pei, T., Zhang, M., Gao, Z., Li, L., Bing, Z., Meng, J., Nwanade, C. F., Yuan, C., Yu, Z., & Liu, J. (2024) · Figshare · doi:10.6084/m9.figshare.26719581
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676947
Tan, W. J., Hawley, H. R., Wilson, S. J., & Fitzsimons, H. L. (2024) · Figshare · doi:10.6084/m9.figshare.24934250
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.25150685
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676953
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676956
Tan, W. J., Hawley, H. R., Wilson, S. J., & Fitzsimons, H. L. (2024) · Figshare · doi:10.6084/m9.figshare.24934704
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676968
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676950
Tan, W. J., Hawley, H. R., Wilson, S. J., & Fitzsimons, H. L. (2024) · Figshare · doi:10.6084/m9.figshare.26659282
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676959
Giorgio, E. D., Paluvai, H., Dalla, E., Ranzino, L., Renzini, A., Moresi, V., Minisini, M., Picco, R., & Brancolini, C. (2021) · Figshare · doi:10.6084/m9.figshare.14562731
Giorgio, E. D., Paluvai, H., Dalla, E., Ranzino, L., Renzini, A., Moresi, V., Minisini, M., Picco, R., & Brancolini, C. (2021) · Figshare · doi:10.6084/m9.figshare.14562755
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676962
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.25150509
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676971
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676944
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676965
SHAO, R., Suzuki, T., Suyama, M., & Tsukada, Y.-I. (2024) · Figshare · doi:10.6084/m9.figshare.26676941
Multifaceted roles of HDAC7 in disease and the evolving chemical toolkit for its modulation
Nie, W., Ding, B., Chen, X., Jiang, L., He, Q., Cao, J., & Zhu, C.-L. (2025) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2025.130510
Wang, M., Fan, J., Mu, B., Zeng, Y., Sun, Y., Zhang, H., Dong, L., Lv, S., Li, S., Ma, X., et al. (2026) · British Journal of Cancer · doi:10.1038/s41416-025-03328-3
The role of histone deacetylase 3 (HDAC3) during megakaryopoiesis
Ishaq, R. (2020) · theses.fr (ABES) · doi:10.70675/08096a2ez3ccaz4219za256zfb0a9d758e0e
SIK3-HDAC4-Warts Axis Functions as a Gatekeeper of Neural Stem Cell Reactivation in DrosophilaPreprint
Gao, Y., Ng, A. Y. E., Lin, J., & Wang, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.04.11.717884
Fiorentino, F., Bontempi, G., Michetti, F., Pecci, V., Fabbrizi, E., Passeri, D., Corsetti, L., Farini, V., Casano, F., Gioiello, A., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02737
Hydroxamic Acids as HDAC Inhibitor Drug Leads for Malaria
Dawood, W. A., Macdonald, J. R., Anzenhofer, C., Skinner‐Adams, T. S., Reid, R. C., Kurz, T., Fairlie, D. P., & Andrews, K. T. (2026) · Medicinal Research Reviews · doi:10.1002/med.70055
Chen, Y., Zhu, J., Qian, J., Li, S., & Liu, Y. (2026) · Biomedicines · doi:10.3390/biomedicines14081692
Investigation of the classical histone deacetylases and sirtuins using peptide technologies
Rogers, J. M., & Olsen, C. A. (2026) · Cell chemical biology · doi:10.1016/j.chembiol.2026.08.009
Structural and Enzymatic Basis for Impaired Deacylation of N -Acyl- N -Methyl Lysine Residues
Hilscher, S., Böttcher, P. H., Friedrich, F., Pannek, M., Baselious, F., Meleshin, M., Einsle, O., Bařinka, C., Steegborn, C., Sippl, W., et al. (2026) · Biochemistry · doi:10.1021/acs.biochem.6c00508 · Cited by 1
Research Progress of Histone Deacetylase and Its Inhibitors in Endometriosis
Xiong, S., Xu, J., Pu, J., Zhao, S., & Jiang, L. (2026) · Reproductive Sciences · doi:10.1007/s43032-026-02184-7
Min, J., Sun, L., Luo, C., Feng, L., Zhao, Y., Yin, Y., & Zhang, W. (2026) · The FASEB Journal · doi:10.1096/fj.202602952r
Liu, K.-Y., Zhao, X., Liu, J., Li, M.-N., Cui, H., Wang, Z., & Zhou, X. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1951750
Histone deacetylases, the erasers of the code
Lamberti, M. J., Vera, R. E., Mentucci, F. M., Vittar, N. B. R., & Schneider, G. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-19001-8.00012-x
BindingDB (2016) · UC San Diego · doi:10.7270/q2qf8rpq
BindingDB (2016) · UC San Diego · doi:10.7270/q29c700v
BindingDB (2010) · UC San Diego · doi:10.7270/q2nz87qh
BindingDB (2017) · UC San Diego · doi:10.7270/q2s184fm
BindingDB Entry 3576: Chemical phylogenetics of histone deacetylases.
BindingDB (2011) · UC San Diego · doi:10.7270/q2c53j66
BindingDB (2010) · UC San Diego · doi:10.7270/q2j966f8
BindingDB (2008) · UC San Diego · doi:10.7270/q2rj4gsk
Metadata
- Authors
- Lahm, A., Paolini, C., Pallaoro, M., Nardi, M. C., Jones, P., Neddermann, P., Sambucini, S., Bottomley, M. J., Lo Surdo, P., Carfı́, A., Koch, U., De Francesco, R., Steinkühler, C., & Gallinari, P.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Istituto di Ricerche di Biologia Molecolare, I.R.B.M., P. Angeletti, 00040 Pomezia, Italy
- Corresponding author
- Gallinari, P.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2007-10-30
- Volume
- 104
- Issue
- 44
- Pages
- 17335-17340
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2077257
- OpenAlex
- W2152631096
- Cited by
- 566
- References
- 36
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 40 · 2023: 15 · 2022: 32 · 2021: 33 · 2020: 32 · 2019: 37 · 2018: 31 · 2017: 29 · 2016: 31 · 2015: 44 · 2014: 29 · 2013: 39 · 2012: 34
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- class IIa histone deacetylases, HDAC4, HDAC5, HDAC7, HDAC9, catalytic efficiency, histone deacetylase inhibitors, class I HDACs, catalytic tyrosine, enzyme evolution, substrate specificity
- MeSH terms
- Amino Acid Sequence, Animals, Binding Sites, Catalysis, Enzyme Activation, HeLa Cells, Histidine, Histone Deacetylases, Humans, Models, Molecular, Mutation, Substrate Specificity, Urochordata, Vertebrates, Protein Structure, Tertiary
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