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Phylogenetic comparison between Type IX Secretion System (T9SS) protein components suggests evidence of horizontal gene transfer

Emrizal R, Nor Muhammad NA

PeerJ, 2020;8:e9019.
PMID: 32617187 DOI: 10.7717/peerj.9019

Porphyromonas gingivalis is one of the major bacteria that causes periodontitis. Chronic periodontitis is a severe form of periodontal disease that ultimately leads to tooth loss. Virulence factors that contribute to periodontitis are secreted by Type IX Secretion System (T9SS). There are aspects of T9SS protein components that have yet to be characterised. Thus, the aim of this study is to investigate the phylogenetic relationship between members of 20 T9SS component protein families. The Bayesian Inference (BI) trees for 19 T9SS protein components exhibit monophyletic clades for all major classes under Bacteroidetes with strong support for the monophyletic clades or its subclades that is consistent with phylogeny exhibited by the constructed BI tree of 16S rRNA. The BI tree of PorR is different from the 19 BI trees of T9SS protein components as it does not exhibit monophyletic clades for all major classes under Bacteroidetes. There is strong support for the phylogeny exhibited by the BI tree of PorR which deviates from the phylogeny based on 16S rRNA. Hence, it is possible that the porR gene is subjected to horizontal transfer as it is known that virulence factor genes could be horizontally transferred. Seven genes (porR included) that are involved in the biosynthesis of A-LPS are found to be flanked by insertion sequences (IS5 family transposons). Therefore, the intervening DNA segment that contains the porR gene might be transposed and subjected to conjugative transfer. Thus, the seven genes can be co-transferred via horizontal gene transfer. The BI tree of UgdA does not exhibit monophyletic clades for all major classes under Bacteroidetes which is similar to the BI tree of PorR (both are a part of the seven genes). Both BI trees also exhibit similar topology as the four identified clusters with strong support and have similar relative positions to each other in both BI trees. This reinforces the possibility that porR and the other six genes might be horizontally transferred. Other than the BI tree of PorR, the 19 other BI trees of T9SS protein components also exhibit evidence of horizontal gene transfer. However, their genes might undergo horizontal gene transfer less frequently compared to porR because the intervening DNA segment that contains porR is easily exchanged between bacteria under Bacteroidetes due to the presence of insertion sequences (IS5 family transposons) that flank it. In conclusion, this study can provide a better understanding about the phylogeny of T9SS protein components.
Fulltext Data on RNA-seq analysis of the cocoa pod borer pest Conopomorpha cramerella (Snellen) (Lepidoptera: Gracillariidae)

Nor Muhammad NA, Ramlee IA, Mohd Nor D, Satyavenathan MV, Rahmat NL, Awang A, et al.

Data Brief, 2021 Feb;34:106638.
PMID: 33365368 DOI: 10.1016/j.dib.2020.106638

Cocoa bean (Theobroma cacao L.) is part of the global cocoa and chocolate industry valued at 44 billion US dollars in 2019. Cocoa pod borer (CPB), Conopomorpha cramerella is a major pest of cocoa in Malaysia and Indonesia that is responsible for the decline for cocoa production. They have been detected since 1980s. Unfortunately, current control strategies are inefficient for CPB management. Although biotechnological alternatives, including RNA interference (RNAi), have been proposed in recent years to control insect pests, characterizing the genetics of the target pest is essential for successful application of these emerging technologies. We generated a comprehensive RNA-seq dataset (135,915,430 clean reads) for larva and adult stages of CPB by using the Illumina HiseqTM 4000 system to increase the understanding of CPB in relation to molecular features. The CPB transcriptome was assembled de novo and annotated. The final assembled produced 249,280 unigenes, of which 75,929 unigenes annotated against NCBI NR database and were distributed among 156 KEGG pathways. The raw data were uploaded to SRA database and the BioProject ID is PRJNA553611. The transcriptomic dataset we present are the first reports of transcriptome information in CPB that is valuable for further exploration and understanding of CPB molecular pathways.
Fulltext PCOSBase: a manually curated database of polycystic ovarian syndrome

Afiqah-Aleng N, Harun S, A-Rahman MRA, Nor Muhammad NA, Mohamed-Hussein ZA

Database (Oxford), 2017 Jan 01;2017.
PMID: 31725861 DOI: 10.1093/database/bax098

Polycystic ovarian syndrome (PCOS) is one of the main causes of infertility and affects 5-20% women of reproductive age. Despite the increased prevalence of PCOS, the mechanisms involved in its pathogenesis and pathophysiology remains unclear. The expansion of omics on studying the mechanisms of PCOS has lead into vast amounts of proteins related to PCOS resulting to a challenge in collating and depositing this deluge of data into one place. A knowledge-based repository named as PCOSBase was developed to systematically store all proteins related to PCOS. These proteins were compiled from various online databases and published expression studies. Rigorous criteria were developed to identify those that were highly related to PCOS. They were manually curated and analysed to provide additional information on gene ontologies, pathways, domains, tissue localizations and diseases that associate with PCOS. Other proteins that might interact with PCOS-related proteins identified from this study were also included. Currently, 8185 PCOS-related proteins were identified and assigned to 13 237 gene ontology vocabulary, 1004 pathways, 7936 domains, 29 disease classes, 1928 diseases, 91 tissues and 320 472 interactions. All publications related to PCOS are also indexed in PCOSBase. Data entries are searchable in the main page, search, browse and datasets tabs. Protein advanced search is provided to search for specific proteins. To date, PCOSBase has the largest collection of PCOS-related proteins. PCOSBase aims to become a self-contained database that can be used to further understand the PCOS pathogenesis and towards the identification of potential PCOS biomarkers. Database URL: http://pcosbase.org.
Fulltext Insight into plant cell wall degradation and pathogenesis of Ganoderma boninense via comparative genome analysis

Ramzi AB, Che Me ML, Ruslan US, Baharum SN, Nor Muhammad NA

PeerJ, 2019;7:e8065.
PMID: 31879570 DOI: 10.7717/peerj.8065

Background: G. boninense is a hemibiotrophic fungus that infects oil palms (Elaeis guineensis Jacq.) causing basal stem rot (BSR) disease and consequent massive economic losses to the oil palm industry. The pathogenicity of this white-rot fungus has been associated with cell wall degrading enzymes (CWDEs) released during saprophytic and necrotrophic stage of infection of the oil palm host. However, there is a lack of information available on the essentiality of CWDEs in wood-decaying process and pathogenesis of this oil palm pathogen especially at molecular and genome levels.
Methods: In this study, comparative genome analysis was carried out using the G. boninense NJ3 genome to identify and characterize carbohydrate-active enzyme (CAZymes) including CWDE in the fungal genome. Augustus pipeline was employed for gene identification in G. boninense NJ3 and the produced protein sequences were analyzed via dbCAN pipeline and PhiBase 4.5 database annotation for CAZymes and plant-host interaction (PHI) gene analysis, respectively. Comparison of CAZymes from G. boninense NJ3 was made against G. lucidum, a well-studied model Ganoderma sp. and five selected pathogenic fungi for CAZymes characterization. Functional annotation of PHI genes was carried out using Web Gene Ontology Annotation Plot (WEGO) and was used for selecting candidate PHI genes related to cell wall degradation of G. boninense NJ3.
Results: G. boninense was enriched with CAZymes and CWDEs in a similar fashion to G. lucidum that corroborate with the lignocellulolytic abilities of both closely-related fungal strains. The role of polysaccharide and cell wall degrading enzymes in the hemibiotrophic mode of infection of G. boninense was investigated by analyzing the fungal CAZymes with necrotrophic Armillaria solidipes, A. mellea, biotrophic Ustilago maydis, Melampsora larici-populina and hemibiotrophic Moniliophthora perniciosa. Profiles of the selected pathogenic fungi demonstrated that necrotizing pathogens including G. boninense NJ3 exhibited an extensive set of CAZymes as compared to the more CAZymes-limited biotrophic pathogens. Following PHI analysis, several candidate genes including polygalacturonase, endo β-1,3-xylanase, β-glucanase and laccase were identified as potential CWDEs that contribute to the plant host interaction and pathogenesis.
Discussion: This study employed bioinformatics tools for providing a greater understanding of the biological mechanisms underlying the production of CAZymes in G. boninense NJ3. Identification and profiling of the fungal polysaccharide- and lignocellulosic-degrading enzymes would further facilitate in elucidating the infection mechanisms through the production of CWDEs by G. boninense. Identification of CAZymes and CWDE-related PHI genes in G. boninense would serve as the basis for functional studies of genes associated with the fungal virulence and pathogenicity using systems biology and genetic engineering approaches.
Ensemble-based, high-throughput virtual screening of potential inhibitor targeting putative farnesol dehydrogenase of Metisa plana (Lepidoptera: Psychidae)

Zifruddin AN, Mohamad Yusoff MA, Abd Ghani NS, Nor Muhammad NA, Lam KW, Hassan M

Comput Biol Chem, 2023 Apr;103:107811.
PMID: 36645937 DOI: 10.1016/j.compbiolchem.2023.107811

Metisa plana (Lepidoptera: Psychidae) bagworm is a leaf-eater caterpillar ubiquitously found as a damaging pest in oil palm plantations, specifically in Malaysia. Various strategies have been implemented, including the usage of chemical insecticides. However, the main challenges include the development of insecticide resistance and its detrimental effects on the environment and non-target organisms. Therefore, a biorational insecticide is introduced by targeting the juvenile hormone (JH) biosynthetic pathway, which is mainly present in the insect and vital for the insect's growth, diapause, metamorphosis, and adult reproduction. This study aimed to investigate the potential inhibitor for the rate-limiting enzyme involved in the JH pathway known as farnesol dehydrogenase. A 255 amino acids sequence encoded for the putative M. plana farnesol dehydrogenase (MpFolDH) open reading frame had been identified and isolated. The three-dimensional structure of MpFolDH was predicted to have seven β- sheets with α-helices at both sides, showing typical characteristics for classical short-chain dehydrogenase and associated with oxidoreductase activity. Then, the ensemble-based virtual screening was conducted based on the ZINC20 database, in which 43 768 compounds that fulfilled pesticide-likeness criteria were screened by site-specific molecular docking. After a short molecular dynamics simulation (5 ns) was conducted towards 102 compounds, only the top 10 compounds based on their most favourable binding energy were selected for a more extended simulation (100 ns). Based on the protein-ligand stability, protein compactness, residues rigidity, binding interaction, binding energy throughout the 100 ns simulation, and physicochemical analysis, ZINC000408743205 was selected as a potential inhibitor for this enzyme. Amino acids decomposition analysis indicates Ile18, Ala95, Val198 and Val202 were the critical contributor residues for MpFolDH-inhibitors(s) complex.
Dissecting the Biology of Rafflesia Species: Current Progress and Future Directions Made Possible with High-Throughput Sequencing Data

Mursyidah AK, Hafizzudin-Fedeli M, Nor Muhammad NA, Latiff A, Firdaus-Raih M, Wan KL

Plant Cell Physiol, 2023 Apr 17;64(4):368-377.
PMID: 36611267 DOI: 10.1093/pcp/pcad004

The angiosperm Rafflesia exhibits a unique biology, including a growth strategy that involves endophytic parasitism of a specific host, with only the gigantic flower externally visible. The Rafflesia possesses many unique evolutionary, developmental and morphological features that are rooted in yet-to-be-explained physiological processes. Although studies on the molecular biology of Rafflesia are limited by sampling difficulties due to its rarity in the wild and the short life span of its flower, current advances in high-throughput sequencing technology have allowed for the genome- and transcriptome-level dissection of the molecular mechanisms behind the unique characteristics of this parasitic plant. In this review, we summarize major findings on the cryptic biology of Rafflesia and provide insights into future research directions. The wealth of data obtained can improve our understanding of Rafflesia species and contribute toward the conservation strategy of this endangered plant.
Fulltext Systematic Multi-Omics Integration (MOI) Approach in Plant Systems Biology

Jamil IN, Remali J, Azizan KA, Nor Muhammad NA, Arita M, Goh HH, et al.

Front Plant Sci, 2020;11:944.
PMID: 32754171 DOI: 10.3389/fpls.2020.00944

Across all facets of biology, the rapid progress in high-throughput data generation has enabled us to perform multi-omics systems biology research. Transcriptomics, proteomics, and metabolomics data can answer targeted biological questions regarding the expression of transcripts, proteins, and metabolites, independently, but a systematic multi-omics integration (MOI) can comprehensively assimilate, annotate, and model these large data sets. Previous MOI studies and reviews have detailed its usage and practicality on various organisms including human, animals, microbes, and plants. Plants are especially challenging due to large poorly annotated genomes, multi-organelles, and diverse secondary metabolites. Hence, constructive and methodological guidelines on how to perform MOI for plants are needed, particularly for researchers newly embarking on this topic. In this review, we thoroughly classify multi-omics studies on plants and verify workflows to ensure successful omics integration with accurate data representation. We also propose three levels of MOI, namely element-based (level 1), pathway-based (level 2), and mathematical-based integration (level 3). These MOI levels are described in relation to recent publications and tools, to highlight their practicality and function. The drawbacks and limitations of these MOI are also discussed for future improvement toward more amenable strategies in plant systems biology.
Towards consolidated bioprocessing of biomass and plastic substrates for semi-synthetic production of bio-poly(ethylene furanoate) (PEF) polymer using omics-guided construction of artificial microbial consortia

Omar MN, Minggu MM, Nor Muhammad NA, Abdul PM, Zhang Y, Ramzi AB

Enzyme Microb Technol, 2024 Jun;177:110429.
PMID: 38537325 DOI: 10.1016/j.enzmictec.2024.110429

Poly(ethylene furanoate) (PEF) plastic is a 100% renewable polyester that is currently being pursued for commercialization as the next-generation bio-based plastic. This is in line with growing demand for circular bioeconomy and new plastics economy that is aimed at minimizing plastic waste mismanagement and lowering carbon footprint of plastics. However, the current catalytic route for the synthesis of PEF is impeded with technical challenges including high cost of pretreatment and catalyst refurbishment. On the other hand, the semi-biosynthetic route of PEF plastic production is of increased biotechnological interest. In particular, the PEF monomers (Furan dicarboxylic acid and ethylene glycol) can be synthesized via microbial-based biorefinery and purified for subsequent catalyst-mediated polycondensation into PEF. Several bioengineering and bioprocessing issues such as efficient substrate utilization and pathway optimization need to be addressed prior to establishing industrial-scale production of the monomers. This review highlights current advances in semi-biosynthetic production of PEF monomers using consolidated waste biorefinery strategies, with an emphasis on the employment of omics-driven systems biology approaches in enzyme discovery and pathway construction. The roles of microbial protein transporters will be discussed, especially in terms of improving substrate uptake and utilization from lignocellulosic biomass, as well as from depolymerized plastic waste as potential bio-feedstock. The employment of artificial bioengineered microbial consortia will also be highlighted to provide streamlined systems and synthetic biology strategies for bio-based PEF monomer production using both plant biomass and plastic-derived substrates, which are important for circular and new plastics economy advances.
Exploring gene regulation and biological processes in insects: Insights from omics data using gene regulatory network models

Chee FT, Harun S, Mohd Daud K, Sulaiman S, Nor Muhammad NA

Prog Biophys Mol Biol, 2024 Apr 09;189:1-12.
PMID: 38604435 DOI: 10.1016/j.pbiomolbio.2024.04.002

Gene regulatory network (GRN) comprises complicated yet intertwined gene-regulator relationships. Understanding the GRN dynamics will unravel the complexity behind the observed gene expressions. Insect gene regulation is often complicated due to their complex life cycles and diverse ecological adaptations. The main interest of this review is to have an update on the current mathematical modelling methods of GRNs to explain insect science. Several popular GRN architecture models are discussed, together with examples of applications in insect science. In the last part of this review, each model is compared from different aspects, including network scalability, computation complexity, robustness to noise and biological relevancy.
Modeling and computational characterization of a Xanthomonas sp. Hypothetical protein identifies a remote ortholog of Burkholderia lethal factor 1

Muhamad Ismail NAS, Yap SH, Mohamad Yussoff MA, Nor Muhammad NA, Firdaus-Raih M, Quay DHX

J Biomol Struct Dyn, 2023;41(13):6027-6039.
PMID: 35862639 DOI: 10.1080/07391102.2022.2100827

Burkholderia Lethal Factor 1 (BLF1) is a deamidase first characterized in Burkholderia pseudomallei. This enzyme inhibits cellular protein synthesis by deamidating a glutamine residue to a glutamic acid in its target protein, the eukaryotic translation initiation factor 4 A (eIF4A). In this work, we present the characterization of a hypothetical protein from Xanthomonas sp. Leaf131 as the first report of a BLF1 family ortholog outside of the Burkholderia genus. Although standard sequence similarity searches such as BLAST were not able to detect the homology between the Xanthomonas sp. Leaf131 hypothetical protein sequence and BLF1, our computed structure model for the Xanthomonas sp. hypothetical protein revealed structural similarities with an RMSD of 2.7 Å/164 Cα atoms and a TM-score of 0.72 when superposed. Structural comparisons of the Xanthomonas model structure against BLF1 and Escherichia coli cytotoxic necrotizing factor 1 (CNF1) revealed that the conserved signature LXGC motif and putative catalytic residues are structurally aligned thus signifying a level of functional or mechanistic similarity. Protein-protein docking analysis and molecular dynamics simulations also demonstrated that eIF4A could still be a possible target substrate for deamidation by XLF1 as it is for BLF1. We therefore propose that this Xanthomonas hypothetical protein be renamed as Xanthomonas Lethal Factor 1 (XLF1). Our work also provides further evidence of the utility of programs such as AlphaFold in bridging the computational function annotation transfer gap despite very low sequence identities of under 20%.Communicated by Ramaswamy H. Sarma.
Transcriptome analysis reveals mechanisms of metabolic detoxification and immune responses following farnesyl acetate treatment in Metisa plana

Rahmat NL, Zifruddin AN, Yusoff NS, Sulaiman S, Zainal Abidin CMR, Othman NW, et al.

Comput Biol Chem, 2024 Oct;112:108176.
PMID: 39181100 DOI: 10.1016/j.compbiolchem.2024.108176

Metisa plana is a widespread insect pest infesting oil palm plantations in Malaysia. Farnesyl acetate (FA), a juvenile hormone analogue, has been reported to exert in vitro and in vivo insecticidal activity against other insect pests. However, the insecticidal mechanism of FA on M. plana remains unclear. Therefore, this study aims to elucidate responsive genes in M. plana in response to FA treatment. The RNA-sequencing reads of FA-treated M. plana were de novo-assembled with existing raw reads from non-treated third instar larvae, and 55,807 transcripts were functionally annotated to multiple protein databases. Several insecticide detoxification-related genes were differentially regulated among the 321 differentially expressed transcripts. Cytochrome P450 monooxygenase, carboxylesterase, and ATP-binding cassette protein were upregulated, while peptidoglycan recognition protein was downregulated. Innate immune response genes, such as glutathione S-transferases, acetylcholinesterase, and heat shock protein, were also identified in the transcriptome. The findings signify that changes occurred in the insect's receptor and signaling, metabolic detoxification of insecticides, and immune responses upon FA treatment on M. plana. This valuable information on FA toxicity may be used to formulate more effective biorational insecticides for better M. plana pest management strategies in oil palm plantations.
Fulltext Nature's Secret Neuro-Regeneration Pathway in Axolotls, Polychaetes and Planarians for Human Therapeutic Target Pathways

Mansor NI, Balqis TN, Lani MN, Lye KL, Nor Muhammad NA, Ismail WIW, et al.

Int J Mol Sci, 2024 Nov 06;25(22).
PMID: 39595973 DOI: 10.3390/ijms252211904

Despite significant improvements in the comprehension of neuro-regeneration, restoring nerve injury in humans continues to pose a substantial therapeutic difficulty. In the peripheral nervous system (PNS), the nerve regeneration process after injury relies on Schwann cells. These cells play a crucial role in regulating and releasing different extracellular matrix proteins, including laminin and fibronectin, which are essential for facilitating nerve regeneration. However, during regeneration, the nerve is required to regenerate for a long distance and, subsequently, loses its capacity to facilitate regeneration during this progression. Meanwhile, it has been noted that nerve regeneration has limited capabilities in the central nervous system (CNS) compared to in the PNS. The CNS contains factors that impede the regeneration of axons following injury to the axons. The presence of glial scar formation results from this unfavourable condition, where glial cells accumulate at the injury site, generating a physical and chemical barrier that hinders the regeneration of neurons. In contrast to humans, several species, such as axolotls, polychaetes, and planarians, possess the ability to regenerate their neural systems following amputation. This ability is based on the vast amount of pluripotent stem cells that have the remarkable capacity to differentiate and develop into any cell within their body. Although humans also possess these cells, their numbers are extremely limited. Examining the molecular pathways exhibited by these organisms has the potential to offer a foundational understanding of the human regeneration process. This review provides a concise overview of the molecular pathways involved in axolotl, polychaete, and planarian neuro-regeneration. It has the potential to offer a new perspective on therapeutic approaches for neuro-regeneration in humans.
Fulltext Computationally Designed Anti-LuxP DNA Aptamer Suppressed Flagellar Assembly- and Quorum Sensing-Related Gene Expression in Vibrio parahaemolyticus

Yusof NAM, Razali SA, Mohd Padzil A, Lau BYC, Baharum SN, Nor Muhammad NA, et al.

Biology (Basel), 2022 Nov 01;11(11).
PMID: 36358301 DOI: 10.3390/biology11111600

(1) Background: Quorum sensing (QS) is the chemical communication between bacteria that sense chemical signals in the bacterial population to control phenotypic changes through the regulation of gene expression. The inhibition of QS has various potential applications, particularly in the prevention of bacterial infection. QS can be inhibited by targeting the LuxP, a periplasmic receptor protein that is involved in the sensing of the QS signaling molecule known as the autoinducer 2 (AI-2). The sensing of AI-2 by LuxP transduces the chemical information through the inner membrane sensor kinase LuxQ protein and activates the QS cascade. (2) Methods: An in silico approach was applied to design DNA aptamers against LuxP in this study. A method combining molecular docking and molecular dynamics simulations was used to select the oligonucleotides that bind to LuxP, which were then further characterized using isothermal titration calorimetry. Subsequently, the bioactivity of the selected aptamer was examined through comparative transcriptome analysis. (3) Results: Two aptamer candidates were identified from the ITC, which have the lowest dissociation constants (Kd) of 0.2 and 0.5 micromolar. The aptamer with the lowest Kd demonstrated QS suppression and down-regulated the flagellar-assembly-related gene expression. (4) Conclusions: This study developed an in silico approach to design an aptamer that possesses anti-QS properties.

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