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  1. Article ; Online: Exploring the diverse role of pyruvate kinase M2 in cancer: Navigating beyond glycolysis and the Warburg effect.

    Upadhyay, Saurabh / Khan, Shumayila / Hassan, Md Imtaiyaz

    Biochimica et biophysica acta. Reviews on cancer

    2024  Volume 1879, Issue 3, Page(s) 189089

    Abstract: Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has ... ...

    Abstract Pyruvate Kinase M2, a key enzyme in glycolysis, has garnered significant attention in cancer research due to its pivotal role in the metabolic reprogramming of cancer cells. Originally identified for its association with the Warburg effect, PKM2 has emerged as a multifaceted player in cancer biology. The functioning of PKM2 is intricately regulated at multiple levels, including controlling the gene expression via various transcription factors and non-coding RNAs, as well as adding post-translational modifications that confer distinct functions to the protein. Here, we explore the diverse functions of PKM2, encompassing newly emerging roles in non-glycolytic metabolic regulation, immunomodulation, inflammation, DNA repair and mRNA processing, beyond its canonical role in glycolysis. The ever-expanding list of its functions has recently grown to include roles in subcellular compartments such as the mitochondria and extracellular milieu as well, all of which make PKM2 an attractive drug target in the pursuit of therapeutics for cancer.
    Language English
    Publishing date 2024-03-06
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 2918802-7
    ISSN 1879-2561 ; 0304-419X
    ISSN (online) 1879-2561
    ISSN 0304-419X
    DOI 10.1016/j.bbcan.2024.189089
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Characterization of E121K mutation of D-amino acid oxidase - Insights into mechanisms leading to amyotrophic lateral sclerosis.

    Dave, Upma / Khan, Shumayila / Gomes, James

    Biochimica et biophysica acta. Proteins and proteomics

    2023  Volume 1871, Issue 6, Page(s) 140947

    Abstract: D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing ... ...

    Abstract D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing study by our group, E121K mutation in DAO was associated with amyotrophic lateral sclerosis (ALS) in patients from India. However, variations in molecular mechanisms caused by this mutation which leads to ALS have not been studied. Hence, we carried out comparative biophysical characterization and assay studies of the wildtype- and mutant E121K-DAO. We observed that the purified E121K-DAO was inactive and exhibited a lower affinity for the FAD cofactor and benzoate inhibitor. Structural studies revealed that the E121K mutant has higher beta-sheet content, melting temperature, and oligomeric states compared to the wildtype. Kinetic study of aggregation of the variants using thioflavin-T confirmed that the E121K-DAO was more prone to aggregation. Microscopic visualization showed that the aggregation proceeds through an intermediate step involving the formation of fibrillar structures in the E121K mutant. Our results give insights into the underlying mechanisms leading to ALS pathogenesis.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/genetics ; Mutation ; Amino Acids/genetics ; Oxidoreductases/genetics ; India
    Chemical Substances Amino Acids ; Oxidoreductases (EC 1.-)
    Language English
    Publishing date 2023-08-07
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2918798-9
    ISSN 1878-1454 ; 1570-9639
    ISSN (online) 1878-1454
    ISSN 1570-9639
    DOI 10.1016/j.bbapap.2023.140947
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Characterization of E121K mutation of D-amino acid oxidase – Insights into mechanisms leading to amyotrophic lateral sclerosis

    Dave, Upma / Khan, Shumayila / Gomes, James

    BBA - Proteins and Proteomics. 2023 Aug. 07, p.140947-

    2023  , Page(s) 140947–

    Abstract: D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing ... ...

    Abstract D-amino acid oxidase (DAO) maintains the intracellular d-serine level which modulates the activity of the N-methyl-d-aspartate receptor and its dysfunction has been linked to several neurodegenerative disorders. In targeted next-generation sequencing study by our group, E121K mutation in DAO was associated with amyotrophic lateral sclerosis (ALS) in patients from India. However, variations in molecular mechanisms caused by this mutation which leads to ALS have not been studied. Hence, we carried out comparative biophysical characterization and assay studies of the wildtype- and mutant E121K-DAO. We observed that the purified E121K-DAO was inactive and exhibited a lower affinity for the FAD cofactor and benzoate inhibitor. Structural studies revealed that the E121K mutant has higher beta-sheet content, melting temperature, and oligomeric states compared to the wildtype. Kinetic study of aggregation of the variants using thioflavin-T confirmed that the E121K-DAO was more prone to aggregation. Microscopic visualization showed that the aggregation proceeds through an intermediate step involving the formation of fibrillar structures in the E121K mutant. Our results give insights into the underlying mechanisms leading to ALS pathogenesis.
    Keywords D-amino-acid oxidase ; amyotrophic lateral sclerosis ; mutants ; mutation ; pathogenesis ; proteomics ; serine ; temperature ; India ; ALS ; D-amino acid oxidase mutation ; Enzyme activity ; FAD ; Aggregation ; DAO ; NMDAR ; WT ; AMPA ; SOD1 ; ThT
    Language English
    Dates of publication 2023-0807
    Publishing place Elsevier B.V.
    Document type Article ; Online
    Note Pre-press version
    ZDB-ID 2918798-9
    ISSN 1878-1454 ; 1570-9639
    ISSN (online) 1878-1454
    ISSN 1570-9639
    DOI 10.1016/j.bbapap.2023.140947
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Structural and mechanistic insights into ALS patient derived mutations in D-amino acid oxidase.

    Khan, Shumayila / Upadhyay, Saurabh / Dave, Upma / Kumar, Ashwani / Gomes, James

    International journal of biological macromolecules

    2023  Volume 256, Issue Pt 2, Page(s) 128403

    Abstract: The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms ...

    Abstract The D-amino acid oxidase protein modulates neurotransmission by controlling the levels of D-serine, a co-agonist of N-methyl-D-aspartate receptors. Mutations in the DAO gene have been associated with ALS, with some studies reporting pathogenic mechanisms of the R199W mutation. We have characterized two novel mutations R38H and Q201R found in ALS patients and report certain novel findings related to the R199W mutation. We report the first instance of crystal structure analysis of a patient-derived mutant of DAO, R38H, solved at 2.10 Å. The structure revealed significant perturbations and altered binding with the cofactor (FAD) and the inhibitor benzoate, supported by biochemical assays. Q201R-DAO also exhibited significantly lower ligand binding efficiency. Furthermore, kinetic analysis across all variants revealed reduced oxidase activity and substrate binding. Notably, R38H-DAO exhibited near-WT activity only at high substrate concentrations, while R199W-DAO and Q201R-DAO displayed drastic activity reduction. Additionally, structural perturbations were inferred for R199W-DAO and Q201R-DAO, evident by the higher oligomeric state in the holoenzyme form. We also observed thermal instability in case of R199W-DAO mutant. We hypothesize that the mutant enzymes may be rendered non-functional in a cellular context, potentially leading to NMDAR-associated excitotoxicity. The study provides novel insights into structural and functional aspects of DAO mutations in ALS.
    MeSH term(s) Humans ; Amyotrophic Lateral Sclerosis/genetics ; Kinetics ; Mutation ; Serine/genetics
    Chemical Substances Serine (452VLY9402)
    Language English
    Publishing date 2023-11-28
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 282732-3
    ISSN 1879-0003 ; 0141-8130
    ISSN (online) 1879-0003
    ISSN 0141-8130
    DOI 10.1016/j.ijbiomac.2023.128403
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.B 2374: Show issues Location:
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  5. Article ; Online: Neuropathogenesis of SARS-CoV-2 infection

    Shumayila Khan / James Gomes

    eLife, Vol

    2020  Volume 9

    Abstract: The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming ... ...

    Abstract The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.
    Keywords SARS-CoV-2 ; COVID-19 ; neurotropic behaviour ; neurological disorder ; brain ; stroke ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Neuropathogenesis of SARS-CoV-2 infection.

    Khan, Shumayila / Gomes, James

    eLife

    2020  Volume 9

    Abstract: The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming ... ...

    Abstract The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.
    MeSH term(s) Ageusia/etiology ; Angiotensin-Converting Enzyme 2 ; Betacoronavirus/pathogenicity ; Betacoronavirus/physiology ; Brain/metabolism ; Brain/virology ; COVID-19 ; Cerebrovascular Disorders/etiology ; Coronavirus Infections/complications ; Coronavirus Infections/epidemiology ; Coronavirus Infections/virology ; Encephalitis, Viral/etiology ; Host Microbial Interactions ; Humans ; Models, Neurological ; Nervous System Diseases/etiology ; Nervous System Diseases/physiopathology ; Nervous System Diseases/virology ; Olfaction Disorders/etiology ; Pandemics ; Peptidyl-Dipeptidase A/metabolism ; Pneumonia, Viral/complications ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/virology ; Receptors, Virus/metabolism ; SARS-CoV-2
    Chemical Substances Receptors, Virus ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
    Keywords covid19
    Language English
    Publishing date 2020-07-30
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2687154-3
    ISSN 2050-084X ; 2050-084X
    ISSN (online) 2050-084X
    ISSN 2050-084X
    DOI 10.7554/eLife.59136
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  7. Article: Neuropathogenesis of SARS-CoV-2 infection

    Khan, Shumayila / Gomes, James

    eLife (Cambridge)

    Abstract: The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming ... ...

    Abstract The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.
    Keywords covid19
    Publisher WHO
    Document type Article
    Note WHO #Covidence: #690669
    Database COVID19

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  8. Article ; Online: Neuropathogenesis of SARS-CoV-2 infection

    Khan, Shumayila / Gomes, James

    eLife

    2020  Volume 9

    Abstract: The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming ... ...

    Abstract The COVID-19 pandemic caused by the SARS-CoV-2 has recently emerged as a serious jolt to human life and economy. Initial knowledge established pulmonary complications as the chief symptom, however, the neurological aspect of the disease is also becoming increasingly evident. Emerging reports of encephalopathies and similar ailments with the detection of the virus in the CSF has elicited an urgent need for investigating the possibility of neuroinvasiveness of the virus, which cannot be ruled out given the expression of low levels of ACE2 receptors in the brain. Sensory impairments of the olfactory and gustatory systems have also been reported in a large proportion of the cases, indicating the involvement of the peripheral nervous system. Hence, the possibility of neurological damage caused by the virus demands immediate attention and investigation of the mechanisms involved, so as to customize the treatment of patients presenting with neurological complications.
    Keywords General Biochemistry, Genetics and Molecular Biology ; General Immunology and Microbiology ; General Neuroscience ; General Medicine ; covid19
    Language English
    Publisher eLife Sciences Publications, Ltd
    Publishing country uk
    Document type Article ; Online
    ZDB-ID 2687154-3
    ISSN 2050-084X
    ISSN 2050-084X
    DOI 10.7554/elife.59136
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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