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  1. Ramzi AB
    Adv Exp Med Biol, 2018 11 2;1102:81-95.
    PMID: 30382570 DOI: 10.1007/978-3-319-98758-3_6
    In the modern era of next-generation genomics and Fourth Industrial Revolution, there is a growing demand for translational research that brings about not only impactful research but also potential commercialisation of R- and D-based products. Advancement of metabolic engineering and synthetic biology has put forward a viable and innovative biotechnological platform for bioproduct development especially using microbial chassis. In this chapter, readers will be introduced on the concepts of metabolic engineering, synthetic biology and microbial chassis and the applications of these biological engineering (BioE) components in the advancement of industrial and agricultural biotechnology. Main strategies in employing BioE platform are discussed especially for waste bioconversion and value-added product development. More importantly, this chapter will also discuss current endeavours in integrating systems and synthetic biology for microbial production of natural products by introducing flavonoid biosynthesis genes of Polygonum minus, a medicinally important tropical plant in engineered yeast.
  2. Ramzi AB, Baharum SN, Bunawan H, Scrutton NS
    Front Bioeng Biotechnol, 2020;8:608918.
    PMID: 33409270 DOI: 10.3389/fbioe.2020.608918
    Increasing demands for the supply of biopharmaceuticals have propelled the advancement of metabolic engineering and synthetic biology strategies for biomanufacturing of bioactive natural products. Using metabolically engineered microbes as the bioproduction hosts, a variety of natural products including terpenes, flavonoids, alkaloids, and cannabinoids have been synthesized through the construction and expression of known and newly found biosynthetic genes primarily from model and non-model plants. The employment of omics technology and machine learning (ML) platforms as high throughput analytical tools has been increasingly leveraged in promoting data-guided optimization of targeted biosynthetic pathways and enhancement of the microbial production capacity, thereby representing a critical debottlenecking approach in improving and streamlining natural products biomanufacturing. To this end, this mini review summarizes recent efforts that utilize omics platforms and ML tools in strain optimization and prototyping and discusses the beneficial uses of omics-enabled discovery of plant biosynthetic genes in the production of complex plant-based natural products by bioengineered microbes.
  3. Rusdi NA, Goh HH, Sabri S, Ramzi AB, Mohd Noor N, Baharum SN
    Molecules, 2018 06 06;23(6).
    PMID: 29882808 DOI: 10.3390/molecules23061370
    Polygonum minus (syn. Persicaria minor) is a herbal plant that is well known for producing sesquiterpenes, which contribute to its flavour and fragrance. This study describes the cloning and functional characterisation of PmSTPS1 and PmSTPS2, two sesquiterpene synthase genes that were identified from P. minus transcriptome data mining. The full-length sequences of the PmSTPS1 and PmSTPS2 genes were expressed in the E. coli pQE-2 expression vector. The sizes of PmSTPS1 and PmSTPS2 were 1098 bp and 1967 bp, respectively, with open reading frames (ORF) of 1047 and 1695 bp and encoding polypeptides of 348 and 564 amino acids, respectively. The proteins consist of three conserved motifs, namely, Asp-rich substrate binding (DDxxD), metal binding residues (NSE/DTE), and cytoplasmic ER retention (RxR), as well as the terpene synthase family N-terminal domain and C-terminal metal-binding domain. From the in vitro enzyme assays, using the farnesyl pyrophosphate (FPP) substrate, the PmSTPS1 enzyme produced multiple acyclic sesquiterpenes of β-farnesene, α-farnesene, and farnesol, while the PmSTPS2 enzyme produced an additional nerolidol as a final product. The results confirmed the roles of PmSTPS1 and PmSTPS2 in the biosynthesis pathway of P. minus, to produce aromatic sesquiterpenes.
  4. 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.

  5. Shah FLA, Ramzi AB, Baharum SN, Noor NM, Goh HH, Leow TC, et al.
    Mol Biol Rep, 2019 Dec;46(6):6647-6659.
    PMID: 31535322 DOI: 10.1007/s11033-019-05066-1
    Flavonoids are polyphenols that are important organic chemicals in plants. The health benefits of flavonoids that result in high commercial values make them attractive targets for large-scale production through bioengineering. Strategies such as engineering a flavonoid biosynthetic pathway in microbial hosts provide an alternative way to produce these beneficial compounds. Escherichia coli, Saccharomyces cerevisiae and Streptomyces sp. are among the expression systems used to produce recombinant products, as well as for the production of flavonoid compounds through various bioengineering approaches including clustered regularly interspaced short palindromic repeats (CRISPR)-based genome engineering and genetically encoded biosensors to detect flavonoid biosynthesis. In this study, we review the recent advances in engineering model microbial hosts as being the factory to produce targeted flavonoid compounds.
  6. Ahmad R, Lim CK, Marzuki NF, Goh YK, Azizan KA, Goh YK, et al.
    Molecules, 2020 Dec 16;25(24).
    PMID: 33339375 DOI: 10.3390/molecules25245965
    In solving the issue of basal stem rot diseases caused by Ganoderma, an investigation of Scytalidium parasiticum as a biological control agent that suppresses Ganoderma infection has gained our interest, as it is more environmentally friendly. Recently, the fungal co-cultivation has emerged as a promising method to discover novel antimicrobial metabolites. In this study, an established technique of co-culturing Scytalidium parasiticum and Ganoderma boninense was applied to produce and induce metabolites that have antifungal activity against G. boninense. The crude extract from the co-culture media was applied to a High Performance Liquid Chromatography (HPLC) preparative column to isolate the bioactive compounds, which were tested against G. boninense. The fractions that showed inhibition against G. boninense were sent for a Liquid Chromatography-Time of Flight-Mass Spectrometry (LC-TOF-MS) analysis to further identify the compounds that were responsible for the microbicidal activity. Interestingly, we found that eudistomin I, naringenin 7-O-beta-D-glucoside and penipanoid A, which were present in different abundances in all the active fractions, except in the control, could be the antimicrobial metabolites. In addition, the abundance of fatty acids, such as oleic acid and stearamide in the active fraction, also enhanced the antimicrobial activity. This comprehensive metabolomics study could be used as the basis for isolating biocontrol compounds to be applied in oil palm fields to combat a Ganoderma infection.
  7. Engku Nasrullah Satiman EAF, Ahmad H, Ramzi AB, Abdul Wahab R, Kaderi MA, Wan Harun WHA, et al.
    J Oral Pathol Med, 2020 Oct;49(9):835-841.
    PMID: 32170981 DOI: 10.1111/jop.13014
    Oral squamous cell carcinoma is associated with many known risk factors including tobacco smoking, chronic alcoholism, poor oral hygiene, unhealthy dietary habits and microbial infection. Previous studies have highlighted Candida albicans host tissue infection as a risk factor in the initiation and progression of oral cancer. C albicans invasion induces several cancerous hallmarks, such as activation of proto-oncogenes, induction of DNA damage and overexpression of inflammatory signalling pathways. However, the molecular mechanisms behind these responses remain unclear. A recently discovered fungal toxin peptide, candidalysin, has been reported as an essential molecule in epithelial damage and host recognition of C albicans infection. Candidalysin has a clear role in inflammasome activation and induction of cell damage. Several inflammatory molecules such as IL-6, IL-17, NLRP3 and GM-CSF have been linked to carcinogenesis. Candidalysin is encoded by the ECE1 gene, which has been linked to virulence factors of C albicans such as adhesion, biofilm formation and filamentation properties. This review discusses the recent epidemiological burden of oral cancer and highlights the significance of the ECE1 gene and the ECE1 protein breakdown product, candidalysin in oral malignancy. The immunological and molecular mechanisms behind oral malignancy induced by inflammation and the role of the toxic fungal peptide candidalysin in oral carcinogenesis are explored. With increasing evidence associating C albicans with oral carcinoma, identifying the possible fungal pathogenicity factors including the role of candidalysin can assist in efforts to understand the link between C albicans infection and carcinogenesis, and pave the way for research into therapeutic potentials.
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