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A Database for Enzymes Involved in Novel Post-Translational Modifications Shradha Khater and Debasisa Mohanty*

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A Database for Enzymes Involved in Novel Post-Translational Modifications Shradha Khater and Debasisa Mohanty* Database, 2015, 1–12 doi: 10.1093/database/bav039 Original article Original article novPTMenzy: a database for enzymes involved in novel post-translational modifications Shradha Khater and Debasisa Mohanty* Bioinformatics Centre, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India *Corresponding author: Tel: þ91 11 26703749; Fax: þ91 11 26742125; Email: [email protected] Citation details: Khater,S. and Mohanty,D. novPTMenzy: a database for enzymes involved in novel post-translational modifications. Database (2015) Vol. 2015: article ID bav039; doi:10.1093/database/bav039 Received 7 November 2014; Revised 30 March 2015; Accepted 1 April 2015 Abstract With the recent discoveries of novel post-translational modifications (PTMs) which play important roles in signaling and biosynthetic pathways, identification of such PTM cata- lyzing enzymes by genome mining has been an area of major interest. Unlike well-known PTMs like phosphorylation, glycosylation, SUMOylation, no bioinformatics resources are available for enzymes associated with novel and unusual PTMs. Therefore, we have developed the novPTMenzy database which catalogs information on the sequence, struc- ture, active site and genomic neighborhood of experimentally characterized enzymes involved in five novel PTMs, namely AMPylation, Eliminylation, Sulfation, Hydroxylation and Deamidation. Based on a comprehensive analysis of the sequence and structural features of these known PTM catalyzing enzymes, we have created Hidden Markov Model profiles for the identification of similar PTM catalyzing enzymatic domains in gen- omic sequences. We have also created predictive rules for grouping them into functional subfamilies and deciphering their mechanistic details by structure-based analysis of their active site pockets. These analytical modules have been made available as user friendly search interfaces of novPTMenzy database. It also has a specialized analysis interface for some PTMs like AMPylation and Eliminylation. The novPTMenzy database is a unique resource that can aid in discovery of unusual PTM catalyzing enzymes in newly sequenced genomes. Database URL: http://www.nii.ac.in/novptmenzy.html Introduction ubiquitin and SUMO or the covalent cleavage of peptide Post-translational modifications (PTMs) of proteins are a backbone (1). The modifications play a central role in crucial strategy used by both prokaryotes and eukaryotes intracellular signaling; signaling pathways associated with to modulate and regulate cellular processes. Modification host-pathogen interactions (2) as well as the biosynthesis of proteins can range from the addition of a small chemical of many bioactive natural products like lantibiotics (3) and moiety such as phosphate to the addition of peptides like so enables proteins to acquire new functions. Therefore, VC The Author(s) 2015. Published by Oxford University Press. Page 1 of 12 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. (page number not for citation purposes) Page 2 of 12 Database, Vol. 2015, Article ID bav039 the identification of enzymes involved in novel PTMs by or threonyl residue in a protein (Figure 1). Three separate genome mining has become an area of major interest. The families of enzymes, Filamentation induced by cAMP (Fic) exponential increase in genome sequences and the experi- (13), Glutamine Synthetase Adenyl Transferases mental characterization of a large number of amino acid (GSATase) (14) and Defects in Rab1 recruitment protein modifications in proteins has created a bottleneck in con- A (DrrA) (15) are known to catalyze the AMPylation reac- necting known PTMs to the genes catalyzing them (4). tion. GSATase inhibits the activity of Glutamine Therefore, it is necessary to decipher the various biochem- Synthetase (GS) in the nitrogen metabolism pathway by ical pathways associated with PTM catalyzing enzymes by AMPylation of tyrosine residues (14). AMPylation by Fic in silico genome analysis. PTMs like phosphorylation, and DrrA domains has been shown to be involved in glycosylation, SUMOylation have been characterized the modification of host proteins by virulent pathogens extensively and a number of bioinformatics tools are avail- (13, 15, 16). This regulation of both metabolic and host able for analysis of the enzymes involved in their catalysis. pathogen interaction pathways by AMPylation makes it a O-GLYCBASE (5) and Phosphso.ELM (6) are some topic of special interest. Involvement of Fic domains in examples of databases associated with specific classes of neurotransmission in glial cells (17) and the presence of PTMs. In contrast to these well-known PTMs, no user this domain in multicellular eukaryotes (18) suggest that friendly tools are available for the identification and ana- AMPylation could also have implications for regulation of lysis of enzymes associated with newly discovered novel other biological processes. Computational studies have PTMs (Figure 1) like AMPylation (7) and Eliminylation (8) shown that death on curing (Doc) proteins share sequence and unusual PTMs like Sulfation (9), Hydroxylation (10) similarity with Fic proteins and hence the Fic family is and Deamidation (11). Even though these PTMs occur less quite often annotated as the Fic/Doc family (18, 19). Apart frequently, they play a crucial role in structural and func- from AMPylation, the members of Fic/Doc family have tional diversification of the proteome and their role in been shown to catalyze phosphorylation and phosphocho- expanding the metabolic and signaling capacities of an line transfer (20). Therefore, it is necessary to identify organism cannot be underestimated (12). sequence and structural features which distinguish AMPylators from other non-AMPylating family members. Results from biochemical studies and information from AMPylation available three-dimensional (3D) structures have helped in AMPylation or adenylylation is the covalent transfer of the elucidation of the active site residues and other mechanistic AMP moiety from ATP to the hydroxyl group of a tyrosyl details of AMPylation domains (21–23). Recent studies Figure 1. Schematic representation of five unusual PTMs of proteins. For each PTM chemical structures of the amino acid and modified amino acid have been depicted. Database, Vol. 2015, Article ID bav039 Page 3 of 12 have also revealed that how inhibitory helices in Fic through asparagine and aspartic acid hydroxylation and domains or in their genomic neighbors inhibit AMPylation hence modulate its interactions with other proteins (34). (21, 24). FIH has also been shown to hydroxylate histidine residues in ankyrin repeat domain of tankyrase-2 and could prob- ably be involved in modulation of hypoxic response (35). Eliminylation Thus, aspartic acid or asparagine hydroxylating enzymes Eliminylation is another novel PTM associated with both can also hydroxylate histidine when it is presented in an host pathogen interaction (25–27) and biosynthetic path- appropriate substrate context. Histidine hydroxylation is ways (28, 29). Eliminylation involves b elimination of the also catalyzed by a new class of 2-oxoglutarate (2OG)— phosphate group of phosphoserine (pS) or phosphothreo- dependent oxygenase—ROX (36, 37). Human MYC- nine (pT) converting these amino acids into dehydroala- induced nuclear antigen (MINA53) and Nucleolar protein nine (DHA) or dehydrobutyrine (DHB) (Figure 1). 66 (NO66) have been shown to catalyze hydroxylation on Removal of phosphate by b elimination is catalyzed by histidine residue within ribosomal proteins Rpl27a and novel phosphothreonine lyase enzymes present in patho- Rpl8, respectively (36, 37). Escherichia coli homolog YcfD genic bacteria like Shigella, Pseudomonas syringae and has been shown to catalyze hydroxylation on arginine resi- Salmonella (25–27). These bacterial phosphothreonine due of ribosomal protein Rpl16 (36–38). Therefore, lyases catalyze the irreversible PTM of host Mitogen- enzymes catalyzing hydroxylation of protein residues con- activated protein kinases (MAPKs) by eliminylation of stitute another important class of PTM catalyzing functionally crucial phosphothreonines, converting them enzymes. to DHB. Since these MAPKs cannot be phosphorylated again, this pathogen-mediated PTM results in the inhib- Deamidation ition of the host MAPK signaling pathways. Phosphothreonine lyase domains are also present in LanL In E. coli Cytotoxic Necrotizing Factors CNF1, CNF2, like type III and type IV lanthipeptide synthetases along CNF3 and CNFc cause the deamidation of a glutamine with kinase domains (28). During the biosynthesis of residue to a glutamate, thereby constitutively activating lanthipeptides, these LanL like phosphothreonine lyase host the RhoGTPases (Figure 1)(11). Deamidation by domains act on phosphorylated serine/threonine-rich pep- CNF1 from Uropathogenic E. coli has been implicated tides to produce dehydro amino acids like DHA and DHB. in infections of the urinary tract while CNF2 has been DHA/DHB are subsequently cyclized with cysteine resi- demonstrated to cause diarrhea in calves and lambs (11). dues by lanthionine cyclase enzymes to generate lanthio- Recently, it was shown that CNFc induces apoptosis in nine groups (28, 29) and so these enzymes are also a prostate cancer cell line, making it a potential candidate involved in biosynthesis
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