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Properties of Coronavirus and SARS-CoV-2

Malik YA

Malays J Pathol, 2020 Apr;42(1):3-11.
PMID: 32342926

were identified beginning with the discovery of SARS-CoV in 2002. With the recent detection of SARS-CoV-2, there are now seven human coronaviruses. Those that cause mild diseases are the 229E, OC43, NL63 and HKU1, and the pathogenic species are SARS-CoV, MERS-CoV and SARS-CoV-2 Coronaviruses (order Nidovirales, family Coronaviridae, and subfamily Orthocoronavirinae) are spherical (125nm diameter), and enveloped with club-shaped spikes on the surface giving the appearance of a solar corona. Within the helically symmetrical nucleocapsid is the large positive sense, single stranded RNA. Of the four coronavirus genera (α,β,γ,δ), human coronaviruses (HCoVs) are classified under α-CoV (HCoV-229E and NL63) and β-CoV (MERS-CoV, SARS-CoV, HCoVOC43 and HCoV-HKU1). SARS-CoV-2 is a β-CoV and shows fairly close relatedness with two bat-derived CoV-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21. Even so, its genome is similar to that of the typical CoVs. SARS-CoV and MERS-CoV originated in bats, and it appears to be so for SARS-CoV-2 as well. The possibility of an intermediate host facilitating the emergence of the virus in humans has already been shown with civet cats acting as intermediate hosts for SARS-CoVs, and dromedary camels for MERS-CoV. Human-to-human transmission is primarily achieved through close contact of respiratory droplets, direct contact with the infected individuals, or by contact with contaminated objects and surfaces. The coronaviral genome contains four major structural proteins: the spike (S), membrane (M), envelope (E) and the nucleocapsid (N) protein, all of which are encoded within the 3' end of the genome. The S protein mediates attachment of the virus to the host cell surface receptors resulting in fusion and subsequent viral entry. The M protein is the most abundant protein and defines the shape of the viral envelope. The E protein is the smallest of the major structural proteins and participates in viral assembly and budding. The N protein is the only one that binds to the RNA genome and is also involved in viral assembly and budding. Replication of coronaviruses begin with attachment and entry. Attachment of the virus to the host cell is initiated by interactions between the S protein and its specific receptor. Following receptor binding, the virus enters host cell cytosol via cleavage of S protein by a protease enzyme, followed by fusion of the viral and cellular membranes. The next step is the translation of the replicase gene from the virion genomic RNA and then translation and assembly of the viral replicase complexes. Following replication and subgenomic RNA synthesis, encapsidation occurs resulting in the formation of the mature virus. Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.

Matched MeSH terms: Viral Envelope Proteins/genetics; Viral Matrix Proteins/genetics; Nucleocapsid Proteins/genetics
Fulltext Striatin Gene Polymorphic Variants Are Associated With Salt Sensitive Blood Pressure in Normotensives and Hypertensives

Gupta T, Connors M, Tan JW, Manosroi W, Ahmed N, Ting PY, et al.

Am J Hypertens, 2017 Dec 08;31(1):124-131.
PMID: 28985281 DOI: 10.1093/ajh/hpx146

BACKGROUND: Understanding the interactions between genetics, sodium (Na+) intake, and blood pressure (BP) will help overcome the lack of individual specificity in our current treatment of hypertension. This study had 3 goals: expand on the relationship between striatin gene (STRN) status and salt-sensitivity of BP (SSBP); evaluate the status of Na+ and volume regulating systems by striatin risk allele status; evaluate potential SSBP mechanisms.
METHODS: We assessed the relationship between STRN status in humans (HyperPATH cohort) and SSBP and on volume regulated systems in humans and a striatin knockout mouse (STRN+/-).
RESULTS: The previously identified association between a striatin risk allele and systolic SSBP was demonstrated in a new cohort (P = 0.01). The STRN-SSBP association was significant for the combined cohort (P = 0.003; β = +5.35 mm Hg systolic BP/risk allele) and in the following subgroups: normotensives, hypertensives, men, and older subjects. Additionally, we observed a lower epinephrine level in risk allele carriers (P = 0.014) and decreased adrenal medulla phenylethanolamine N-methyltransferase (PNMT) in STRN+/- mice. No significant associations were observed with other volume regulated systems.
CONCLUSIONS: These results support the association between a variant of striatin and SSBP and extend the findings to normotensive individuals and other subsets. In contrast to most salt-sensitive hypertensives, striatin-associated SSBP is associated with normal plasma renin activity and reduced epinephrine levels. These data provide clues to the underlying cause and a potential pathway to achieve, specific, personalized treatment, and prevention.

Matched MeSH terms: Calmodulin-Binding Proteins/genetics*; Membrane Proteins/genetics*; Nerve Tissue Proteins/genetics*
Phage display antibodies for diagnostic applications

Hairul Bahara NH, Tye GJ, Choong YS, Ong EB, Ismail A, Lim TS

Biologicals, 2013 Jul;41(4):209-16.
PMID: 23647952 DOI: 10.1016/j.biologicals.2013.04.001

With major developments in molecular biology, numerous display technologies have been successfully introduced for recombinant antibody production. Even so, phage display still remains the gold standard for recombinant antibody production. Its success is mainly attributed to the robust nature of phage particles allowing for automation and adaptation to modifications. The generation of monospecific binders provides a vital tool for diagnostics at a lower cost and higher efficiency. The flexibility to modify recombinant antibodies allows great applicability to various platforms for use. This review presents phage display technology, application and modifications of recombinant antibodies for diagnostics.

Matched MeSH terms: Recombinant Proteins/genetics
The red cell 'X'-protein system in goats: evidence for a third allele in a Malaysian breed

Hasima N, Dhaliwal SS, Mukherjee TK

Anim. Genet., 1988;19(1):37-41.
PMID: 3377277

Genetic polymorphism of the 'X'-protein in red cells from Malaysian Katjang goats was demonstrated by starch gel electrophoresis at pH 7.3. Two new phenotypes were observed, suggesting that one new allele is involved. A new nomenclature for the 'X'-protein system in goats is proposed.

Matched MeSH terms: Blood Proteins/genetics*
Focal Segmental Membranoproliferative Glomerulonephritis: A Histological Variant of Denys-Drash Syndrome

Karmila AB, Yap YC, Appadurai M, Oh L, Fazarina M, Abd Ghani F, et al.

Fetal Pediatr Pathol, 2021 Apr;40(2):113-120.
PMID: 31707902 DOI: 10.1080/15513815.2019.1686788

Introduction: Denys-Drash Syndrome (DDS) consists of a triad of pseudohermaphroditism, Wilms'tumor and nephropathy. This condition may manifest as a complete triad or in an incomplete form; with either one or a combination of the above features. The characteristic glomerular abnormality in DDS is diffuse mesangial sclerosis (DMS).Case report: We report two cases of DDS with focal membranoproliferative glomerulonephritis (MPGN). Both of our cases were males with ambiguous genitalia. They had a similar heterozygous germline mutation in exon 9 of WT1, c.1180C>T, p.R394W; a known mutation hotspot for DDS. Case 1 had nephropathy at the age of 4 years and Case 2 at 2.5 years with different rates of progression to end-stage renal failure. Conclusion: Our findings, in combination with other reports, illustrate the clinicopathological heterogeneity of DDS. There are no universal recommendations for optimal management of patients with DDS due to the inability to accurately predict affected individuals' progress.

Matched MeSH terms: WT1 Proteins/genetics
Local acclimatisation-driven differential gene and protein expression patterns of Hsp70 in Acropora muricata: Implications for coral tolerance to bleaching

Louis YD, Bhagooli R, Seveso D, Maggioni D, Galli P, Vai M, et al.

Mol Ecol, 2020 11;29(22):4382-4394.
PMID: 32967057 DOI: 10.1111/mec.15642

Corals show spatial acclimatisation to local environment conditions. However, the various cellular mechanisms involved in local acclimatisation and variable bleaching patterns in corals remain to be thoroughly understood. In this study, the modulation of a protein implicated in cellular heat stress tolerance, the heat shock protein 70, was compared at both gene (hsp70) and protein (Hsp70) expression level in bleaching tolerant near-coast Acropora muricata colonies and bleaching susceptible reef colonies, in the lagoon of Belle Mare (Mauritius). The relative Hsp70 levels varied significantly between colonies from the two different locations, colonies having different health conditions and the year of collection. Before the bleaching event of 2016, near-coast colonies had higher basal levels of both Hsp70 gene and protein compared to reef colonies. During the bleaching event, the near-coast colonies did not bleach and had significantly higher relative levels of both Hsp70 gene and protein compared to bleached reef colonies. No significant genetic differentiation between the two studied coral populations was observed and all the colonies analysed were associated with Symbiodiniaceae of the genus Symbiodinium (Clade A) irrespective of location and sampling period. These findings provide further evidence of the involvement of Hsp70 in conferring bleaching tolerance to corals. Moreover, the consistent expression differences of Hsp70 gene and protein between the near-coast and reef coral populations in a natural setting indicate that the modulation of this Hsp is involved in local acclimatisation of corals to their environments.

Matched MeSH terms: HSP70 Heat-Shock Proteins/genetics
Fulltext Genetic diversity of circumsporozoite protein in Plasmodium knowlesi isolates from Malaysian Borneo and Peninsular Malaysia

Chong ETJ, Neoh JWF, Lau TY, Lim YA, Chai HC, Chua KH, et al.

Malar J, 2020 Oct 22;19(1):377.
PMID: 33092594 DOI: 10.1186/s12936-020-03451-x

BACKGROUND: Understanding the genetic diversity of candidate genes for malaria vaccines such as circumsporozoite protein (csp) may enhance the development of vaccines for treating Plasmodium knowlesi. Hence, the aim of this study is to investigate the genetic diversity of non-repeat regions of csp in P. knowlesi from Malaysian Borneo and Peninsular Malaysia.
METHODS: A total of 46 csp genes were subjected to polymerase chain reaction amplification. The genes were obtained from P. knowlesi isolates collected from different divisions of Sabah, Malaysian Borneo, and Peninsular Malaysia. The targeted gene fragments were cloned into a commercial vector and sequenced, and a phylogenetic tree was constructed while incorporating 168 csp sequences retrieved from the GenBank database. The genetic diversity and natural evolution of the csp sequences were analysed using MEGA6 and DnaSP ver. 5.10.01. A genealogical network of the csp haplotypes was generated using NETWORK ver. 4.6.1.3.
RESULTS: The phylogenetic analysis revealed indistinguishable clusters of P. knowlesi isolates across different geographic regions, including Malaysian Borneo and Peninsular Malaysia. Nucleotide analysis showed that the csp non-repeat regions of zoonotic P. knowlesi isolates obtained in this study underwent purifying selection with population expansion, which was supported by extensive haplotype sharing observed between humans and macaques. Novel variations were observed in the C-terminal non-repeat region of csp.
CONCLUSIONS: The csp non-repeat regions are relatively conserved and there is no distinct cluster of P. knowlesi isolates from Malaysian Borneo and Peninsular Malaysia. Distinctive variation data obtained in the C-terminal non-repeat region of csp could be beneficial for the design and development of vaccines to treat P. knowlesi.

Matched MeSH terms: Protozoan Proteins/genetics*
Functional evaluation of a recombinant fungal immunomodulatory protein from L. rhinocerus produced in P. pastoris and E. coli host expression systems

Ejike UC, Chan CJ, Lim CSY, Lim RLH

Appl Microbiol Biotechnol, 2021 Apr;105(7):2799-2813.
PMID: 33763709 DOI: 10.1007/s00253-021-11225-x

Fungal immunomodulatory proteins (FIPs) are bioactive proteins with immunomodulatory properties. We previously reported the heterologous production in Escherichia coli of FIP-Lrh from Tiger milk mushroom (Lignosus rhinocerus) with potent cytotoxic effect on cancer cell lines. However, protein produced in E. coli lacks post-translational modifications and may be contaminated with lipopolysaccharide (LPS) endotoxin. Therefore, in this study, yFIP-Lrh produced in Pichia pastoris was functionally compared with eFIP-Lrh produced in E. coli. Expression construct of FIP-Lrh cDNA in pPICZα was generated, transformed into P. pastoris X-33 and Mut+ transformants were verified by colony PCR. Induction with 0.5% or 1% methanol resulted in a secreted 13.6 kDa yFIP-Lrh which was subsequently purified and verified using LCMS/MS analysis. Size exclusion chromatography confirmed eFIP-Lrh as a homodimer whereas the larger size of yFIP-Lrh may indicate post-translational modification despite negative for glycoproteins staining. At lower concentration (4-8 μg/mL), yFIP-Lrh induced significantly higher Th1 (IFN-γ, TNF-α) and Th2 (IL-6, IL-4, IL-5, IL-13) cytokines production in mice splenocytes, whereas 16 μg/mL eFIP-Lrh induced significantly higher pro-inflammatory cytokines (TNF-α, IL-6, IL-10), possibly due to higher residual LPS endotoxin (0.082 EU/mL) in eFIP-Lrh compared to negligible level in yFIP-Lrh (0.001 EU/mL). Furthermore, yFIP-Lrh showed higher cytotoxic effect on MCF-7 and HeLa cancer cells. Since both recombinant proteins of FIP-Lrh have the same peptide sequence, besides glycosylation, other post-translational modifications in yFIP-Lrh may account for its enhanced immunomodulatory and anti-proliferative activities. In conclusion, P. pastoris is preferred over E. coli for production of a functionally active yFIP-Lrh devoid of endotoxin contamination. KEY POINTS: • FIP-Lrh can induced production of Th1 and Th2 cytokines by mouse splenocytes. • Higher cytotoxic effect on cancer cells observed for yeast compared to E. coli produced FIP-Lrh. • P. pastoris allows production of an endotoxin-free and functionally active recombinant FIP-Lrh.

Matched MeSH terms: Recombinant Proteins/genetics
Fulltext Genomic characterization of bacteria from the ultra-oligotrophic Madison aquifer: insight into the archetypical LuxI/LuxR and identification of novel LuxR solos

Wengert PC, Wong NH, Barton HA, Gan HM, Hudson AO, Savka MA

BMC Res Notes, 2021 May 08;14(1):175.
PMID: 33964980 DOI: 10.1186/s13104-021-05589-6

OBJECTIVES: To characterize the bacterial community of Wind Cave's Madison aquifer through whole-genome sequencing, and to better understand the bacterial ecology by identifying genes involved in acyl-homoserine lactone (AHL) based quorum-sensing (QS) systems.
RESULTS: Genome-based taxonomic classification revealed the microbial richness present in the pristine Madison aquifer. The strains were found to span eleven genera and fourteen species, of which eight had uncertain taxonomic classifications. The genomes of strains SD129 and SD340 were found to contain the archetypical AHL QS system composed of two genes, luxI and luxR. Surprisingly, the genomes of strains SD115, SD129, SD274 and SD316 were found to contain one to three luxR orphans (solos). Strain SD129, besides possessing an archetypical AHL QS luxI-luxR pair, also contained two luxR solos, while strain SD316 contained three LuxR solos and no luxI-luxR pairs. The ligand-binding domain of two LuxR solos, one each from strains SD129 and SD316, were found to contain novel substitutions not previously reported, thus may represent two LuxR orphans that detection and response to unknown self-produced signal(s), or to signal(s) produced by other organisms.

Matched MeSH terms: Bacterial Proteins/genetics
A preliminary proteomic study of permethrin resistant and susceptible Aedes aegypti (L.)

Rosilawati R, Nabila R, Siti Futri Farahininajua F, Nazni WA, Lee HL

Trop Biomed, 2019 Dec 01;36(4):855-865.
PMID: 33597458

The mechanism of insecticide resistance is traditionally attributed to detoxification enzymes, target site alteration, decreased penetration of insecticides and behavioural resistance. Other form of mechanisms, such as the role of protein(s) in resistance is unknown. In the present study, the protein profiling of both IMR-PSS strain (permethrin-selected) and IMR-LS strain (laboratory-susceptible) 24 hours post exposure period to permethrin was carried out via 1D-gel electrophoresis and liquid chromatography mass spectrometry (LC-MS/ MS). The bands which appeared in the gel of 1D-electrophoresis revealed an abundance of proteins. The band pattern of both strains looked macroscopically alike and differed only in band intensity. However, LC-MS/MS analysis revealed that the IMR-PSS strain produced extra 388 peptides that were not found in the IMR-LS strain, indicating that IMR-PSS strain reacted differently from IMR-LS strain as a result of persistent exposure to permethrin. Since the complex banding patterns of 1D-gel electrophoresis were difficult to interpret the significance of the protein difference between IMR-PSS and IMR-LS strain, hence LC-MS/MS analysis is ideally suited for better protein resolution and thus will allow more in-depth comparison of the complex pattern. The findings here provide the first preliminary evidence that insecticide resistance in mosquito induces up regulation of proteins that may be protective to mosquitoes against insecticide and proteins could be another mechanism that contributes to development of resistance.

Matched MeSH terms: Insect Proteins/genetics
Complete genome sequencing revealed novel genetic contexts of the mcr-1 gene in Escherichia coli strains

Yu CY, Ang GY, Chong TM, Chin PS, Ngeow YF, Yin WF, et al.

J Antimicrob Chemother, 2017 04 01;72(4):1253-1255.
PMID: 28031273 DOI: 10.1093/jac/dkw541
Matched MeSH terms: Escherichia coli Proteins/genetics*
Structural probing of HapR to identify potent phytochemicals to control Vibrio cholera through integrated computational approaches

Tahir Ul Qamar M, Ahmad S, Khan A, Mirza MU, Ahmad S, Abro A, et al.

Comput Biol Med, 2021 11;138:104929.
PMID: 34655900 DOI: 10.1016/j.compbiomed.2021.104929

Cholera is a severe small intestine bacterial disease caused by consumption of water and food contaminated with Vibrio cholera. The disease causes watery diarrhea leading to severe dehydration and even death if left untreated. In the past few decades, V. cholerae has emerged as multidrug-resistant enteric pathogen due to its rapid ability to adapt in detrimental environmental conditions. This research study aimed to design inhibitors of a master virulence gene expression regulator, HapR. HapR is critical in regulating the expression of several set of V. cholera virulence genes, quorum-sensing circuits and biofilm formation. A blind docking strategy was employed to infer the natural binding tendency of diverse phytochemicals extracted from medicinal plants by exposing the whole HapR structure to the screening library. Scoring function criteria was applied to prioritize molecules with strong binding affinity (binding energy

Matched MeSH terms: Bacterial Proteins/genetics
VapC toxin switches M. smegmatis cells into dormancy through 23S rRNA cleavage

Zamakhaev M, Grigorov A, Bespyatykh J, Azhikina T, Goncharenko A, Shumkov M

Arch Microbiol, 2022 Dec 15;205(1):28.
PMID: 36520276 DOI: 10.1007/s00203-022-03363-1

Mycobacterium tuberculosis is an extremely successful pathogen known for its ability to cause latent infection. The latter is connected with the bacterium resting state development and is considered to be based on the activity of toxin-antitoxin (TA) systems at least in part. Here we studied the physiological and proteomic consequences of VapC toxin overexpression together with the features of the protein synthesis apparatus and compared them with the characteristics of dormant mycobacterial cells in an M. smegmatis model. The findings allow suggesting the mechanism mycobacteria enter dormancy, which is realized through VapC-caused cleavage of the 23S rRNA Sarcin-Ricin loop followed by conservation of stalled ribosomes in a membrane-associated manner. The found features of resting mycobacteria protein synthesis apparatus hypothesize the mechanisms of resuscitation from dormancy through the ribosomes de-association off the membrane accompanied by the 23S rRNA break curing, and could be of value for the development of principally new antituberculosis agents.

Matched MeSH terms: Bacterial Proteins/genetics
Fulltext Genetic Diversity and Clustering of the Rhoptry Associated Protein-1 of Plasmodium knowlesi from Peninsular Malaysia and Malaysian Borneo

Azlan UW, Lau YL, Fong MY

Korean J Parasitol, 2022 Dec;60(6):393-400.
PMID: 36588415 DOI: 10.3347/kjp.2022.60.6.393

Human infection with simian malaria Plasmodium knowlesi is a cause for concern in Southeast Asian countries, especially in Malaysia. A previous study on Peninsular Malaysia P. knowlesi rhoptry associated protein-1 (PkRAP1) gene has discovered the existence of dimorphism. In this study, genetic analysis of PkRAP1 in a larger number of P. knowlesi samples from Malaysian Borneo was conducted. The PkRAP1 of these P. knowlesi isolates was PCR-amplified and sequenced. The newly obtained PkRAP1 gene sequences (n = 34) were combined with those from the previous study (n = 26) and analysed for polymorphism and natural selection. Sequence analysis revealed a higher genetic diversity of PkRAP1 compared to the previous study. Exon II of the gene had higher diversity (π = 0.0172) than exon I (π = 0.0128). The diversity of the total coding region (π = 0.0167) was much higher than those of RAP1 orthologues such as PfRAP-1 (π = 0.0041) and PvRAP1 (π = 0.00088). Z-test results indicated that the gene was under purifying selection. Phylogenetic tree and haplotype network showed distinct clustering of Peninsular Malaysia and Malaysian Borneo PkRAP1 haplotypes. This geographical-based clustering of PkRAP1 haplotypes provides further evidence of the dimorphism of the gene and possible existence of 2 distinct P. knowlesi lineages in Malaysia.

Matched MeSH terms: Protozoan Proteins/genetics
Fulltext Genetic polymorphism of the thrombospondin-related apical merozoite protein (TRAMP) of Plasmodium knowlesi in Malaysia

Ng YL, Lau YL, Hamid MHA, Jelip J, Ooi CH, Mudin RN, et al.

Parasitol Res, 2023 Jan;122(1):195-200.
PMID: 36378331 DOI: 10.1007/s00436-022-07716-z

Plasmodium knowlesi is a simian malaria parasite that causes significant zoonotic infections in Southeast Asia, particularly in Malaysia. The Plasmodium thrombospondin-related apical merozoite protein (TRAMP) plays an essential role in the invasion of the parasite into its host erythrocyte. The present study investigated the genetic polymorphism and natural selection of the full length PkTRAMP from P. knowlesi clinical isolates from Malaysia. Blood samples (n = 40) were collected from P. knowlesi malaria patients from Peninsular Malaysia and Malaysian Borneo. The PkTRAMP gene was amplified using PCR, followed by cloning into a plasmid vector and sequenced. Results showed that the nucleotide diversity of PkTRAMP was low (π: 0.009). Z-test results indicated negative (purifying) selection of PkTRAMP. The alignment of the deduced amino acid sequences of PkTRAMP of Peninsular Malaysia and Malaysian Borneo revealed 38 dimorphic sites. A total of 27 haplotypes were identified from the amino acid sequence alignment. Haplotype analysis revealed that there was no clustering of PkTRAMP from Peninsular Malaysia and Malaysian Borneo.

Matched MeSH terms: Protozoan Proteins/genetics
Fulltext Biofilm Signaling, Composition and Regulation in Burkholderia pseudomallei

Nyanasegran PK, Nathan S, Firdaus-Raih M, Muhammad NAN, Ng CL

J Microbiol Biotechnol, 2023 Jan 28;33(1):15-27.
PMID: 36451302 DOI: 10.4014/jmb.2207.07032

The incidence of melioidosis cases caused by the gram-negative pathogen Burkholderia pseudomallei (BP) is seeing an increasing trend that has spread beyond its previously known endemic regions. Biofilms produced by BP have been associated with antimicrobial therapy limitation and relapse melioidosis, thus making it urgently necessary to understand the mechanisms of biofilm formation and their role in BP biology. Microbial cells aggregate and enclose within a self-produced matrix of extracellular polymeric substances (EPSs) to form biofilm. The transition mechanism of bacterial cells from planktonic state to initiate biofilm formation, which involves the formation of surface attachment microcolonies and the maturation of the biofilm matrix, is a dynamic and complex process. Despite the emerging findings on the biofilm formation process, systemic knowledge on the molecular mechanisms of biofilm formation in BP remains fractured. This review provides insights into the signaling systems, matrix composition, and the biosynthesis regulation of EPSs (exopolysaccharide, eDNA and proteins) that facilitate the formation of biofilms in order to present an overview of our current knowledge and the questions that remain regarding BP biofilms.

Matched MeSH terms: Bacterial Proteins/genetics
In silico analysis prediction of HepTH1-5 as a potential therapeutic agent by targeting tumour suppressor protein networks

Azemin WA, Alias N, Ali AM, Shamsir MS

J Biomol Struct Dyn, 2023 Mar;41(4):1141-1167.
PMID: 34935583 DOI: 10.1080/07391102.2021.2017349

Many studies reported that the activation of tumour suppressor protein, p53 induced the human hepcidin expression. However, its expression decreased when p53 was silenced in human hepatoma cells. Contrary to Tilapia hepcidin TH1-5, HepTH1-5 was previously reported to trigger the p53 activation through the molecular docking approach. The INhibitor of Growth (ING) family members are also shown to directly interact with p53 and promote cell cycle arrest, senescence, apoptosis and participate in DNA replication and DNA damage responses to suppress the tumour initiation and progression. However, the interrelation between INGs and HepTH1-5 remains unknown. Therefore, this study aims to identify the mechanism and their protein interactions using in silico approaches. The finding revealed that HepTH1-5 and its ligands had interacted mostly on hotspot residues of ING proteins which involved in histone modifications via acetylation, phosphorylation, and methylation. This proves that HepTH1-5 might implicate in an apoptosis signalling pathway and preserve the protein structure and function of INGs by reducing the perturbation of histone binding upon oxidative stress response. This study would provide theoretical guidance for the design and experimental studies to decipher the role of HepTH1-5 as a potential therapeutic agent for cancer therapy. Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Tumor Suppressor Proteins/genetics
LYRM7-associated mitochondrial complex III deficiency with non-cavitating leukoencephalopathy and stroke-like episodes

Alfattal R, Alfarhan M, Algaith AM, Albash B, Elshafie RM, Alshammari A, et al.

Am J Med Genet A, 2023 May;191(5):1401-1411.
PMID: 36757047 DOI: 10.1002/ajmg.a.63143

Defects of respiratory chain complex III (CIII) result in characteristic but rare mitochondrial disorders associated with distinct neuroradiological findings. The underlying molecular defects affecting mitochondrial CIII assembly factors are few and yet to be identified. LYRM7 assembly factor is required for proper CIII assembly where it acts as a chaperone for the Rieske iron-sulfur (UQCRFS1) protein in the mitochondrial matrix and stabilizing it. We present here the seventeenth individual with LYRM7-associated mitochondrial leukoencephalopathy harboring a previously reported rare pathogenic homozygous LYRM 7 variant, c.2T>C, (p.Met1?). Like previously reported individuals, our 5-year-old male proband presented with recurrent metabolic and lactic acidosis, encephalopathy, and fatigue. Further, he has additional, previously unreported features, including an acute stroke like episode with bilateral central blindness and optic neuropathy, recurrent hyperglycemia and hypertension associated with metabolic crisis. However, he has no signs of psychomotor regression. He has been stable clinically with residual left-sided reduced visual acuity and amblyopia, and no more metabolic crises for 2-year-period while on the mitochondrial cocktail. Although the reported brain MRI findings in other affected individuals are homogenous, it is slightly different in our index, revealing evidence of bilateral almost symmetric multifocal periventricular T2 hyperintensities with hyperintensities of the optic nerves, optic chiasm, and corona radiata but with no cavitation or cystic changes. This report describes new clinical and radiological findings of LYRM7-associated disease. The report also summarizes the clinical and molecular data of previously reported individuals describing the full phenotypic spectrum.

Matched MeSH terms: Mitochondrial Proteins/genetics
Fulltext Type II bacterial toxin-antitoxins: hypotheses, facts, and the newfound plethora of the PezAT system

Chan WT, Garcillán-Barcia MP, Yeo CC, Espinosa M

FEMS Microbiol Rev, 2023 Sep 05;47(5).
PMID: 37715317 DOI: 10.1093/femsre/fuad052

Toxin-antitoxin (TA) systems are entities found in the prokaryotic genomes, with eight reported types. Type II, the best characterized, is comprised of two genes organized as an operon. Whereas toxins impair growth, the cognate antitoxin neutralizes its activity. TAs appeared to be involved in plasmid maintenance, persistence, virulence, and defence against bacteriophages. Most Type II toxins target the bacterial translational machinery. They seem to be antecessors of Higher Eukaryotes and Prokaryotes Nucleotide-binding (HEPN) RNases, minimal nucleotidyltransferase domains, or CRISPR-Cas systems. A total of four TAs encoded by Streptococcus pneumoniae, RelBE, YefMYoeB, Phd-Doc, and HicAB, belong to HEPN-RNases. The fifth is represented by PezAT/Epsilon-Zeta. PezT/Zeta toxins phosphorylate the peptidoglycan precursors, thereby blocking cell wall synthesis. We explore the body of knowledge (facts) and hypotheses procured for Type II TAs and analyse the data accumulated on the PezAT family. Bioinformatics analyses showed that homologues of PezT/Zeta toxin are abundantly distributed among 14 bacterial phyla mostly in Proteobacteria (48%), Firmicutes (27%), and Actinobacteria (18%), showing the widespread distribution of this TA. The pezAT locus was found to be mainly chromosomally encoded whereas its homologue, the tripartite omega-epsilon-zeta locus, was found mostly on plasmids. We found several orphan pezT/zeta toxins, unaccompanied by a cognate antitoxin.

Matched MeSH terms: Bacterial Proteins/genetics
In silico identification and characterization of potential druggable targets among hypothetical proteins of Leptospira interrogans serovar Copenhageni: a comprehensive bioinformatics approach

Siddiqui Q, Ali MSM, Leow ATC, Oslan SN, Mohd Shariff F

J Biomol Struct Dyn, 2023 Dec;41(20):10347-10367.
PMID: 36510668 DOI: 10.1080/07391102.2022.2154845

Leptospirosis is one of the neglected zoonosis, affecting human and animal populations worldwide. Reliable effective therapeutics and concerns to look for more research into the molecular analysis of its genome is therefore needed. In the genomic pool of the Leptospira interrogans many hypothetical proteins are still uncharacterized. In the current research, we performed extensive in silico analysis to prioritize the potential hypothetical proteins of L. interrogans serovar Copenhageni via stepwise reducing the available hypothetical proteins (Total 3606) of the assembly to only 15, based on non-homologous to homosapien, essential, functional, virulent, cellular localization. Out of them, only two proteins WP_000898918.1 (Hypothetical Protein 1) & WP_001014594.1 (Hypothetical Protein 2) were found druggable and involved in protein-protein interaction network. The 3 D structures of these two target proteins were predicted via ab initio homology modeling followed by structures refinement and validation, as no structures were available till date. The analysis also revealed that the functional domains, families and protein-protein interacting partners identified in both proteins are crucial for the survival of the bacteria. The binding cavities were predicted for both the proteins through blind and specific protein-ligand docking with their respective ligands and inhibitors and were found to be in accordance with the druggable sites predicted by DoGSiteScorer. The docking interactions were found within the active functional domains for both the proteins while for Hypothetical Protein 2, the same residues were involved in interactions with Cytidine-5'-triphosphate in blind and specific docking. Furthermore, the simulations of molecular dynamics and free binding energy revealed the stable substrate binding and efficient binding energies, and were in accordance to our docking results. The work predicted two unique hypothetical proteins of L. interrogans as a potential druggable targets for designing of inhibitors for them.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Bacterial Proteins/genetics

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