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Unravelling the adaptation strategies employed by Glaciozyma antarctica PI12 on Antarctic sea ice

Bharudin I, Abu Bakar MF, Hashim NHF, Mat Isa MN, Alias H, Firdaus-Raih M, et al.

Mar Environ Res, 2018 Jun;137:169-176.
PMID: 29598997 DOI: 10.1016/j.marenvres.2018.03.007

Glaciozyma antarctica PI12, is a psychrophilic yeast isolated from Antarctic sea. In this work, Expressed Sequence Tags (EST) from cells exposed to three different temperatures; 15 °C, 0 °C and -12 °C were generated to identify genes associated with cold adaptation. A total of 5376 clones from each library were randomly picked and sequenced. Comparative analyses from the resulting ESTs in each condition identified several groups of genes required for cold adaptation. Additionally, 319 unique transcripts that encoded uncharacterised functions were identified in the -12 °C library and are currently unique to G. antarctica. Gene expression analysis using RT-qPCR revealed two of the unknown genes to be up-regulated at -12 °C compared to 0 °C and 15 °C. These findings further contribute to the collective knowledge into G. antarctica cold adaptation and as a resource for understanding the ecological and physiological tolerance of psychrophilic microbes in general.
Biochemical and in silico structural characterization of a cold-active arginase from the psychrophilic yeast, Glaciozyma antarctica PI12

Yusof NY, Quay DHX, Kamaruddin S, Jonet MA, Md Illias R, Mahadi NM, et al.

Extremophiles, 2024 Feb 01;28(1):15.
PMID: 38300354 DOI: 10.1007/s00792-024-01333-7

Glaciozyma antarctica PI12 is a psychrophilic yeast isolated from Antarctica. In this work, we describe the heterologous production, biochemical properties and in silico structure analysis of an arginase from this yeast (GaArg). GaArg is a metalloenzyme that catalyses the hydrolysis of L-arginine to L-ornithine and urea. The cDNA of GaArg was reversed transcribed, cloned, expressed and purified as a recombinant protein in Escherichia coli. The purified protein was active against L-arginine as its substrate in a reaction at 20 °C, pH 9. At 10-35 °C and pH 7-9, the catalytic activity of the protein was still present around 50%. Mn2+, Ni2+, Co2+ and K+ were able to enhance the enzyme activity more than two-fold, while GaArg is most sensitive to SDS, EDTA and DTT. The predicted structure model of GaArg showed a very similar overall fold with other known arginases. GaArg possesses predominantly smaller and uncharged amino acids, fewer salt bridges, hydrogen bonds and hydrophobic interactions compared to the other counterparts. GaArg is the first reported arginase that is cold-active, facilitated by unique structural characteristics for its adaptation of catalytic functions at low-temperature environments. The structure and function of cold-active GaArg provide insights into the potentiality of new applications in various biotechnology and pharmaceutical industries.
Fulltext COGNAC: a web server for searching and annotating hydrogen-bonded base interactions in RNA three-dimensional structures

Firdaus-Raih M, Hamdani HY, Nadzirin N, Ramlan EI, Willett P, Artymiuk PJ

Nucleic Acids Res, 2014 Jul;42(Web Server issue):W382-8.
PMID: 24831543 DOI: 10.1093/nar/gku438

Hydrogen bonds are crucial factors that stabilize a complex ribonucleic acid (RNA) molecule's three-dimensional (3D) structure. Minute conformational changes can result in variations in the hydrogen bond interactions in a particular structure. Furthermore, networks of hydrogen bonds, especially those found in tight clusters, may be important elements in structure stabilization or function and can therefore be regarded as potential tertiary motifs. In this paper, we describe a graph theoretical algorithm implemented as a web server that is able to search for unbroken networks of hydrogen-bonded base interactions and thus provide an accounting of such interactions in RNA 3D structures. This server, COGNAC (COnnection tables Graphs for Nucleic ACids), is also able to compare the hydrogen bond networks between two structures and from such annotations enable the mapping of atomic level differences that may have resulted from conformational changes due to mutations or binding events. The COGNAC server can be accessed at http://mfrlab.org/grafss/cognac.
Fulltext Comparative sequence and structure analysis reveals the conservation and diversity of nucleotide positions and their associated tertiary interactions in the riboswitches

Appasamy SD, Ramlan EI, Firdaus-Raih M

PLoS One, 2013;8(9):e73984.
PMID: 24040136 DOI: 10.1371/journal.pone.0073984

The tertiary motifs in complex RNA molecules play vital roles to either stabilize the formation of RNA 3D structure or to provide important biological functionality to the molecule. In order to better understand the roles of these tertiary motifs in riboswitches, we examined 11 representative riboswitch PDB structures for potential agreement of both motif occurrences and conservations. A total of 61 unique tertiary interactions were found in the reference structures. In addition to the expected common A-minor motifs and base-triples mainly involved in linking distant regions the riboswitch structures three highly conserved variants of A-minor interactions called G-minors were found in the SAM-I and FMN riboswitches where they appear to be involved in the recognition of the respective ligand's functional groups. From our structural survey as well as corresponding structure and sequence alignments, the agreement between motif occurrences and conservations are very prominent across the representative riboswitches. Our analysis provide evidence that some of these tertiary interactions are essential components to form the structure where their sequence positions are conserved despite a high degree of diversity in other parts of the respective riboswitches sequences. This is indicative of a vital role for these tertiary interactions in determining the specific biological function of riboswitch.
Fulltext IMAAAGINE: a webserver for searching hypothetical 3D amino acid side chain arrangements in the Protein Data Bank

Nadzirin N, Willett P, Artymiuk PJ, Firdaus-Raih M

Nucleic Acids Res, 2013 Jul;41(Web Server issue):W432-40.
PMID: 23716645 DOI: 10.1093/nar/gkt431

We describe a server that allows the interrogation of the Protein Data Bank for hypothetical 3D side chain patterns that are not limited to known patterns from existing 3D structures. A minimal side chain description allows a variety of side chain orientations to exist within the pattern, and generic side chain types such as acid, base and hydroxyl-containing can be additionally deployed in the search query. Moreover, only a subset of distances between the side chains need be specified. We illustrate these capabilities in case studies involving arginine stacks, serine-acid group arrangements and multiple catalytic triad-like configurations. The IMAAAGINE server can be accessed at http://mfrlab.org/grafss/imaaagine/.
Comparative Genome Sequence Analysis Reveals the Extent of Diversity and Conservation for Glycan-Associated Proteins in Burkholderia spp

Ong HS, Mohamed R, Firdaus-Raih M

Comp. Funct. Genomics, 2012;2012:752867.
PMID: 22991502

Members of the Burkholderia family occupy diverse ecological niches. In pathogenic family members, glycan-associated proteins are often linked to functions that include virulence, protein conformation maintenance, surface recognition, cell adhesion, and immune system evasion. Comparative analysis of available Burkholderia genomes has revealed a core set of 178 glycan-associated proteins shared by all Burkholderia of which 68 are homologous to known essential genes. The genome sequence comparisons revealed insights into species-specific gene acquisitions through gene transfers, identified an S-layer protein, and proposed that significantly reactive surface proteins are associated to sugar moieties as a potential means to circumvent host defense mechanisms. The comparative analysis using a curated database of search queries enabled us to gain insights into the extent of conservation and diversity, as well as the possible virulence-associated roles of glycan-associated proteins in members of the Burkholderia spp. The curated list of glycan-associated proteins used can also be directed to screen other genomes for glycan-associated homologs.
Fulltext NASSAM: a server to search for and annotate tertiary interactions and motifs in three-dimensional structures of complex RNA molecules

Hamdani HY, Appasamy SD, Willett P, Artymiuk PJ, Firdaus-Raih M

Nucleic Acids Res, 2012 Jul;40(Web Server issue):W35-41.
PMID: 22661578 DOI: 10.1093/nar/gks513

Similarities in the 3D patterns of RNA base interactions or arrangements can provide insights into their functions and roles in stabilization of the RNA 3D structure. Nucleic Acids Search for Substructures and Motifs (NASSAM) is a graph theoretical program that can search for 3D patterns of base arrangements by representing the bases as pseudo-atoms. The geometric relationship of the pseudo-atoms to each other as a pattern can be represented as a labeled graph where the pseudo-atoms are the graph's nodes while the edges are the inter-pseudo-atomic distances. The input files for NASSAM are PDB formatted 3D coordinates. This web server can be used to identify matches of base arrangement patterns in a query structure to annotated patterns that have been reported in the literature or that have possible functional and structural stabilization implications. The NASSAM program is freely accessible without any login requirement at http://mfrlab.org/grafss/nassam/.
Fulltext SPRITE and ASSAM: web servers for side chain 3D-motif searching in protein structures

Nadzirin N, Gardiner EJ, Willett P, Artymiuk PJ, Firdaus-Raih M

Nucleic Acids Res, 2012 Jul;40(Web Server issue):W380-6.
PMID: 22573174 DOI: 10.1093/nar/gks401

Similarities in the 3D patterns of amino acid side chains can provide insights into their function despite the absence of any detectable sequence or fold similarities. Search for protein sites (SPRITE) and amino acid pattern search for substructures and motifs (ASSAM) are graph theoretical programs that can search for 3D amino side chain matches in protein structures, by representing the amino acid side chains as pseudo-atoms. The geometric relationship of the pseudo-atoms to each other as a pattern can be represented as a labeled graph where the pseudo-atoms are the graph's nodes while the edges are the inter-pseudo-atomic distances. Both programs require the input file to be in the PDB format. The objective of using SPRITE is to identify matches of side chains in a query structure to patterns with characterized function. In contrast, a 3D pattern of interest can be searched for existing occurrences in available PDB structures using ASSAM. Both programs are freely accessible without any login requirement. SPRITE is available at http://mfrlab.org/grafss/sprite/ while ASSAM can be accessed at http://mfrlab.org/grafss/assam/.
Fulltext Proteins of unknown function in the Protein Data Bank (PDB): an inventory of true uncharacterized proteins and computational tools for their analysis

Nadzirin N, Firdaus-Raih M

Int J Mol Sci, 2012;13(10):12761-72.
PMID: 23202924 DOI: 10.3390/ijms131012761

Proteins of uncharacterized functions form a large part of many of the currently available biological databases and this situation exists even in the Protein Data Bank (PDB). Our analysis of recent PDB data revealed that only 42.53% of PDB entries (1084 coordinate files) that were categorized under "unknown function" are true examples of proteins of unknown function at this point in time. The remainder 1465 entries also annotated as such appear to be able to have their annotations re-assessed, based on the availability of direct functional characterization experiments for the protein itself, or for homologous sequences or structures thus enabling computational function inference.
Fulltext Computational discovery and RT-PCR validation of novel Burkholderia conserved and Burkholderia pseudomallei unique sRNAs

Khoo JS, Chai SF, Mohamed R, Nathan S, Firdaus-Raih M

BMC Genomics, 2012;13 Suppl 7:S13.
PMID: 23282220 DOI: 10.1186/1471-2164-13-S7-S13

The sRNAs of bacterial pathogens are known to be involved in various cellular roles including environmental adaptation as well as regulation of virulence and pathogenicity. It is expected that sRNAs may also have similar functions for Burkholderia pseudomallei, a soil bacterium that can adapt to diverse environmental conditions, which causes the disease melioidosis and is also able to infect a wide variety of hosts.
Fulltext InterRNA: a database of base interactions in RNA structures

Appasamy SD, Hamdani HY, Ramlan EI, Firdaus-Raih M

Nucleic Acids Res, 2016 Jan 4;44(D1):D266-71.
PMID: 26553798 DOI: 10.1093/nar/gkv1186

A major component of RNA structure stabilization are the hydrogen bonded interactions between the base residues. The importance and biological relevance for large clusters of base interactions can be much more easily investigated when their occurrences have been systematically detected, catalogued and compared. In this paper, we describe the database InterRNA (INTERactions in RNA structures database-http://mfrlab.org/interrna/) that contains records of known RNA 3D motifs as well as records for clusters of bases that are interconnected by hydrogen bonds. The contents of the database were compiled from RNA structural annotations carried out by the NASSAM (http://mfrlab.org/grafss/nassam) and COGNAC (http://mfrlab.org/grafss/cognac) computer programs. An analysis of the database content and comparisons with the existing corpus of knowledge regarding RNA 3D motifs clearly show that InterRNA is able to provide an extension of the annotations for known motifs as well as able to provide novel interactions for further investigations.
Reconstructing gene regulatory networks from knock-out data using Gaussian Noise Model and Pearson Correlation Coefficient

Mohamed Salleh FH, Arif SM, Zainudin S, Firdaus-Raih M

Comput Biol Chem, 2015 Dec;59 Pt B:3-14.
PMID: 26278974 DOI: 10.1016/j.compbiolchem.2015.04.012

A gene regulatory network (GRN) is a large and complex network consisting of interacting elements that, over time, affect each other's state. The dynamics of complex gene regulatory processes are difficult to understand using intuitive approaches alone. To overcome this problem, we propose an algorithm for inferring the regulatory interactions from knock-out data using a Gaussian model combines with Pearson Correlation Coefficient (PCC). There are several problems relating to GRN construction that have been outlined in this paper. We demonstrated the ability of our proposed method to (1) predict the presence of regulatory interactions between genes, (2) their directionality and (3) their states (activation or suppression). The algorithm was applied to network sizes of 10 and 50 genes from DREAM3 datasets and network sizes of 10 from DREAM4 datasets. The predicted networks were evaluated based on AUROC and AUPR. We discovered that high false positive values were generated by our GRN prediction methods because the indirect regulations have been wrongly predicted as true relationships. We achieved satisfactory results as the majority of sub-networks achieved AUROC values above 0.5.
Fulltext Side chain similarity comparisons for integrated drug repositioning and potential toxicity assessments in epidemic response scenarios: The case for COVID-19

Ab Ghani NS, Emrizal R, Makmur H, Firdaus-Raih M

Comput Struct Biotechnol J, 2020;18:2931-2944.
PMID: 33101604 DOI: 10.1016/j.csbj.2020.10.013

Structures of protein-drug-complexes provide an atomic level profile of drug-target interactions. In this work, the three-dimensional arrangements of amino acid side chains in known drug binding sites (substructures) were used to search for similarly arranged sites in SARS-CoV-2 protein structures in the Protein Data Bank for the potential repositioning of approved compounds. We were able to identify 22 target sites for the repositioning of 16 approved drug compounds as potential therapeutics for COVID-19. Using the same approach, we were also able to investigate the potentially promiscuous binding of the 16 compounds to off-target sites that could be implicated in toxicity and side effects that had not been provided by any previous studies. The investigations of binding properties in disease-related proteins derived from the comparison of amino acid substructure arrangements allows for effective mechanism driven decision making to rank and select only the compounds with the highest potential for success and safety to be prioritized for clinical trials or treatments. The intention of this work is not to explicitly identify candidate compounds but to present how an integrated drug repositioning and potential toxicity pipeline using side chain similarity searching algorithms are of great utility in epidemic scenarios involving novel pathogens. In the case of the COVID-19 pandemic caused by the SARS-CoV-2 virus, we demonstrate that the pipeline can identify candidate compounds quickly and sustainably in combination with associated risk factors derived from the analysis of potential off-target site binding by the compounds to be repurposed.
Regulation of Glycine Cleavage and Detoxification by a Highly Conserved Glycine Riboswitch in Burkholderia spp

Munyati-Othman N, Appasamy SD, Damiri N, Emrizal R, Alipiah NM, Ramlan EI, et al.

Curr Microbiol, 2021 Aug;78(8):2943-2955.
PMID: 34076709 DOI: 10.1007/s00284-021-02550-5

The glycine riboswitch is a known regulatory element that is unique in having two aptamers that are joined by a linker region. In this study, we investigated a glycine riboswitch located in the 5' untranslated region of a glycine cleavage system homolog (gcvTHP) in Burkholderia spp. Structure prediction using the sequence generated a model with a glycine binding pocket composed of base-triple interactions (G62-A64-A86 and G65-U84-C85) that are supported by A/G minor interactions (A17-C60-G88 and G16-C61-G87, respectively) and two ribose-zipper motifs (C11-G12 interacting with A248-A247 and C153-U154 interacting with A79-A78) which had not been previously reported. The capacity of the riboswitch to bind to glycine was experimentally validated by native gel assays and the crucial role of interactions that make up the glycine binding pocket were proven by mutations of A17U and G16C which resulted in conformational differences that may lead to dysfunction. Using glycine supplemented minimal media, we were able to prove that the expression of the gcvTHP genes found downstream of the riboswitch responded to the glycine concentrations introduced thus confirming the role of this highly conserved Burkholderia riboswitch and its associated genes as a putative glycine detoxification system in Burkholderia spp.
Fulltext Graph Theoretical Methods and Workflows for Searching and Annotation of RNA Tertiary Base Motifs and Substructures

Emrizal R, Hamdani HY, Firdaus-Raih M

Int J Mol Sci, 2021 Aug 09;22(16).
PMID: 34445259 DOI: 10.3390/ijms22168553

The increasing number and complexity of structures containing RNA chains in the Protein Data Bank (PDB) have led to the need for automated structure annotation methods to replace or complement expert visual curation. This is especially true when searching for tertiary base motifs and substructures. Such base arrangements and motifs have diverse roles that range from contributions to structural stability to more direct involvement in the molecule's functions, such as the sites for ligand binding and catalytic activity. We review the utility of computational approaches in annotating RNA tertiary base motifs in a dataset of PDB structures, particularly the use of graph theoretical algorithms that can search for such base motifs and annotate them or find and annotate clusters of hydrogen-bond-connected bases. We also demonstrate how such graph theoretical algorithms can be integrated into a workflow that allows for functional analysis and comparisons of base arrangements and sub-structures, such as those involved in ligand binding. The capacity to carry out such automatic curations has led to the discovery of novel motifs and can give new context to known motifs as well as enable the rapid compilation of RNA 3D motifs into a database.
Fulltext Drug ReposER: a web server for predicting similar amino acid arrangements to known drug binding interfaces for potential drug repositioning

Ab Ghani NS, Ramlan EI, Firdaus-Raih M

Nucleic Acids Res, 2019 07 02;47(W1):W350-W356.
PMID: 31106379 DOI: 10.1093/nar/gkz391

A common drug repositioning strategy is the re-application of an existing drug to address alternative targets. A crucial aspect to enable such repurposing is that the drug's binding site on the original target is similar to that on the alternative target. Based on the assumption that proteins with similar binding sites may bind to similar drugs, the 3D substructure similarity data can be used to identify similar sites in other proteins that are not known targets. The Drug ReposER (DRug REPOSitioning Exploration Resource) web server is designed to identify potential targets for drug repurposing based on sub-structural similarity to the binding interfaces of known drug binding sites. The application has pre-computed amino acid arrangements from protein structures in the Protein Data Bank that are similar to the 3D arrangements of known drug binding sites thus allowing users to explore them as alternative targets. Users can annotate new structures for sites that are similarly arranged to the residues found in known drug binding interfaces. The search results are presented as mappings of matched sidechain superpositions. The results of the searches can be visualized using an integrated NGL viewer. The Drug ReposER server has no access restrictions and is available at http://mfrlab.org/drugreposer/.
Fulltext Computational discovery and annotation of conserved small open reading frames in fungal genomes

Mat-Sharani S, Firdaus-Raih M

BMC Bioinformatics, 2019 Feb 04;19(Suppl 13):551.
PMID: 30717662 DOI: 10.1186/s12859-018-2550-2

BACKGROUND: Small open reading frames (smORF/sORFs) that encode short protein sequences are often overlooked during the standard gene prediction process thus leading to many sORFs being left undiscovered and/or misannotated. For many genomes, a second round of sORF targeted gene prediction can complement the existing annotation. In this study, we specifically targeted the identification of ORFs encoding for 80 amino acid residues or less from 31 fungal genomes. We then compared the predicted sORFs and analysed those that are highly conserved among the genomes.
RESULTS: A first set of sORFs was identified from existing annotations that fitted the maximum of 80 residues criterion. A second set was predicted using parameters that specifically searched for ORF candidates of 80 codons or less in the exonic, intronic and intergenic sequences of the subject genomes. A total of 1986 conserved sORFs were predicted and characterized.
CONCLUSIONS: It is evident that numerous open reading frames that could potentially encode for polypeptides consisting of 80 amino acid residues or less are overlooked during standard gene prediction and annotation. From our results, additional targeted reannotation of genomes is clearly able to complement standard genome annotation to identify sORFs. Due to the lack of, and limitations with experimental validation, we propose that a simple conservation analysis can provide an acceptable means of ensuring that the predicted sORFs are sufficiently clear of gene prediction artefacts.
Fulltext Identification of sRNA mediated responses to nutrient depletion in Burkholderia pseudomallei

Mohd-Padil H, Damiri N, Sulaiman S, Chai SF, Nathan S, Firdaus-Raih M

Sci Rep, 2017 12 07;7(1):17173.
PMID: 29215024 DOI: 10.1038/s41598-017-17356-4

The Burkholderia genus includes many species that are known to survive in diverse environmental conditions including low nutrient environments. One species, Burkholderia pseudomallei is a versatile pathogen that can survive in a wide range of hosts and environmental conditions. In this study, we investigated how a nutrient depleted growth environment evokes sRNA mediated responses by B. pseudomallei. Computationally predicted B. pseudomallei D286 sRNAs were mapped to RNA-sequencing data for cultures grown under two conditions: (1) BHIB as a nutrient rich media reference environment and (2) M9 media as a nutrient depleted stress environment. The sRNAs were further selected to identify potentially cis-encoded systems by investigating their possible interactions with their flanking genes. The mappings of predicted sRNA genes and interactions analysis to their flanking genes identified 12 sRNA candidates that may possibly have cis-acting regulatory roles that are associated to a nutrient depleted growth environment. Our approach can be used for identifying novel sRNA genes and their possible role as cis-mediated regulatory systems.
Fulltext GrAfSS: a webserver for substructure similarity searching and comparisons in the structures of proteins and RNA

Ghani NSA, Emrizal R, Moffit SM, Hamdani HY, Ramlan EI, Firdaus-Raih M

Nucleic Acids Res, 2022 Jul 05;50(W1):W375-W383.
PMID: 35639505 DOI: 10.1093/nar/gkac402

The GrAfSS (Graph theoretical Applications for Substructure Searching) webserver is a platform to search for three-dimensional substructures of: (i) amino acid side chains in protein structures; and (ii) base arrangements in RNA structures. The webserver interfaces the functions of five different graph theoretical algorithms - ASSAM, SPRITE, IMAAAGINE, NASSAM and COGNAC - into a single substructure searching suite. Users will be able to identify whether a three-dimensional (3D) arrangement of interest, such as a ligand binding site or 3D motif, observed in a protein or RNA structure can be found in other structures available in the Protein Data Bank (PDB). The webserver also allows users to determine whether a protein or RNA structure of interest contains substructural arrangements that are similar to known motifs or 3D arrangements. These capabilities allow for the functional annotation of new structures that were either experimentally determined or computationally generated (such as the coordinates generated by AlphaFold2) and can provide further insights into the diversity or conservation of functional mechanisms of structures in the PDB. The computed substructural superpositions are visualized using integrated NGL viewers. The GrAfSS server is available at http://mfrlab.org/grafss/.
Fulltext Characterization of Burkholderia pseudomallei protein BPSL1375 validates the Putative hemolytic activity of the COG3176 N-Acyltransferase family

Ahmad L, Hung TL, Mat Akhir NA, Mohamed R, Nathan S, Firdaus-Raih M

BMC Microbiol, 2015;15:270.
PMID: 26597807 DOI: 10.1186/s12866-015-0604-4

There are still numerous protein subfamilies within families and superfamilies that do not yet have conclusive empirical experimental evidence providing a specific function. These proteins persist in databases with the annotation of a specific 'putative' function made by association with discernible features in the protein sequence.

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