Alpha/beta hydrolase domain-containing protein 14B. The general transcription initiation factor TFIID and its interactors play critical roles in regulating the transcription. TFIID interactor CCG1/TAF(II)250-interacting factor B (CIB) activates transcription and has hydrolase activity towards p-nitrophenyl butyrate (in vitro). Dorz1 (ABHD14A,ABHEA) was identified and characterized as one of the most significantly down-regulated genes in Zic1-deficient cerebellum (Zic1: zinc finger protein that controls vertebrate neural development) Crystal structure of predicted CIB-like hydrolase (NP_393672.1) from Thermoplasma acidophilum has also been released. ABHD14B is able to transfer an acetyl group from a post-translationally acetylated-lysine to coenzyme A (CoA) and yield acetyl-CoA, while re-generating the free amine of protein lysine residues (Rajendran et al. 2020): lysine deacetylase
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Interpro
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IPR026764 (Alpha/beta hydrolase domain containing protein 14B)
The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (alpha/beta-hydrolase domain containing protein # 14B) as a novel KDAC, showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A (CoA) to yield acetyl-CoA, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics, and metabolomics analysis. We found from these complementary experiments in vivo, that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice, also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology, and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.
The metabolic serine hydrolase family is, arguably, one of the largest functional enzyme classes in mammals, including humans, comprising 1-2% of the total proteome. This enzyme family uses a conserved nucleophilic serine residue in the active site to perform diverse hydrolytic reactions and consists of proteases, lipases, esterases, amidases, and transacylases, which are prototypical members of this family. In humans, this enzyme family consists of >250, of which approximately 40% members remain unannotated, in terms of both their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAFII250-interacting factor B, as it was found to be associated with transcription initiation factor TFIID. The crystal structure of human ABHD14B was determined more than a decade ago; however, its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme's ability to transfer an acetyl group from a post-translationally acetylated lysine to coenzyme A (CoA), to yield acetyl-CoA, while regenerating the free amine of protein lysine residues. We validate these findings by in vitro biochemical assays using recombinantly purified human ABHD14B in conjunction with cellular studies in a mammalian cell line by knocking down ABHD14B and by identification of a putative substrate binding site. Finally, we report the development and characterization of a much-needed, exquisitely selective ABHD14B antibody, and using it, we map the cellular and tissue distribution of ABHD14B and prospective metabolic pathways that this enzyme might biologically regulate.
The general transcription initiation factor TFIID and its interactors play critical roles in regulating the transcription from both naked and chromatin DNA. We have isolated a novel TFIID interactor that we denoted as CCG1/TAF(II)250-interacting factor B (CIB). We show here that CIB activates transcription. To further understand the function of this protein, we determined its crystal structure at 2.2-Angstroms resolution. The tertiary structure of CIB reveals an alpha/beta-hydrolase fold that resembles structures in the prokaryotic alpha/beta-hydrolase family proteins. It is not similar in structure or primary sequence to any eukaryotic transcription or chromatin factors that have been reported to date. CIB possesses a conserved catalytic triad that is found in other alpha/beta-hydrolases, and our in vitro studies confirmed that it bears hydrolase activity. However, CIB differs from other alpha/beta-hydrolases in that it lacks a binding site excursion, which facilitates the substrate selectivity of the other alpha/beta-hydrolases. Further functional characterization of CIB based on its tertiary structure and through biochemical studies may provide novel insights into the mechanisms that regulate eukaryotic transcription.
The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (alpha/beta-hydrolase domain containing protein # 14B) as a novel KDAC, showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A (CoA) to yield acetyl-CoA, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics, and metabolomics analysis. We found from these complementary experiments in vivo, that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice, also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology, and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.
The metabolic serine hydrolase family is, arguably, one of the largest functional enzyme classes in mammals, including humans, comprising 1-2% of the total proteome. This enzyme family uses a conserved nucleophilic serine residue in the active site to perform diverse hydrolytic reactions and consists of proteases, lipases, esterases, amidases, and transacylases, which are prototypical members of this family. In humans, this enzyme family consists of >250, of which approximately 40% members remain unannotated, in terms of both their endogenous substrates and the biological pathways that they regulate. The enzyme ABHD14B, an outlying member of this family, is also known as CCG1/TAFII250-interacting factor B, as it was found to be associated with transcription initiation factor TFIID. The crystal structure of human ABHD14B was determined more than a decade ago; however, its endogenous substrates remain elusive. In this paper, we annotate ABHD14B as a lysine deacetylase (KDAC), showing this enzyme's ability to transfer an acetyl group from a post-translationally acetylated lysine to coenzyme A (CoA), to yield acetyl-CoA, while regenerating the free amine of protein lysine residues. We validate these findings by in vitro biochemical assays using recombinantly purified human ABHD14B in conjunction with cellular studies in a mammalian cell line by knocking down ABHD14B and by identification of a putative substrate binding site. Finally, we report the development and characterization of a much-needed, exquisitely selective ABHD14B antibody, and using it, we map the cellular and tissue distribution of ABHD14B and prospective metabolic pathways that this enzyme might biologically regulate.
The general transcription initiation factor TFIID and its interactors play critical roles in regulating the transcription from both naked and chromatin DNA. We have isolated a novel TFIID interactor that we denoted as CCG1/TAF(II)250-interacting factor B (CIB). We show here that CIB activates transcription. To further understand the function of this protein, we determined its crystal structure at 2.2-Angstroms resolution. The tertiary structure of CIB reveals an alpha/beta-hydrolase fold that resembles structures in the prokaryotic alpha/beta-hydrolase family proteins. It is not similar in structure or primary sequence to any eukaryotic transcription or chromatin factors that have been reported to date. CIB possesses a conserved catalytic triad that is found in other alpha/beta-hydrolases, and our in vitro studies confirmed that it bears hydrolase activity. However, CIB differs from other alpha/beta-hydrolases in that it lacks a binding site excursion, which facilitates the substrate selectivity of the other alpha/beta-hydrolases. Further functional characterization of CIB based on its tertiary structure and through biochemical studies may provide novel insights into the mechanisms that regulate eukaryotic transcription.
        
Title: Dorz1, a novel gene expressed in differentiating cerebellar granule neurons, is down-regulated in Zic1-deficient mouse Hoshino J, Aruga J, Ishiguro A, Mikoshiba K Ref: Brain Research Mol Brain Res, 120:57, 2003 : PubMed
The Zic1 gene encodes a zinc finger protein that controls vertebrate neural development. A previous study showed that Zic1 is expressed in developing and mature cerebellar granule neurons, and that Zic1-deficient cerebellum is hypoplastic and lacks a lobule of the anterior lobe. In the present study, we searched for genes de-regulated in the cerebellum to understand the molecular basis of cerebellar development. A novel gene, Dorz1, was identified and characterized as one of the most significantly down-regulated genes in Zic1-deficient cerebellum by the DNA microarray analysis. The expression of Dorz1 in the developing cerebellum peaked at embryonic day 17.5, and at that stage Dorz1 transcripts were detected in cerebellar granule neuron precursors where Zic1 expression is enhanced. In addition, Dorz1 expression was up-regulated in cultured cells overexpressing Zic1. These results suggest that Dorz1 expression is positively regulated by Zic1 during cerebellar development.
        
Other Papers
No structure scheme yet for this family
Structures in CIB-CCG1-interacting-factor-B family (2)