Olawale G. Raimi

MRC Protein Phosphorylation and Ubiquitylation Unit

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Daan M. F. van Aalten

University of Dundee

Andrew T. Ferenbach

Aarhus University

Ramón Hurtado‐Guerrero

Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo

Wenxia Fang

Guangxi Academy of Sciences

Deborah Lockhart

University of Aberdeen

Michael A. J. Ferguson

Harvard University

Miratul M. K. Muqit

University of Dundee

Michael D. Urbaniak

Lancaster University

David A. Robinson

Wellcome Centre for Anti-Infectives Research

Hina Ojha

University of Dundee

Cooperative Institutions

University of Dundee

MRC Protein Phosphorylation and Ubiquitylation Unit

Medical Research Council

Wellcome Centre for Anti-Infectives Research

Wellcome Trust

University of York

Guangxi Academy of Sciences

Harvard University

University of Basel

Swiss Tropical and Public Health Institute

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Crystal structure of Aspergillus fumigatus N-acetylphosphoglucosamine mutase in complex with GlcNAc-6P and magnesium

Olawale G. Raimi Ramón Hurtado‐Guerrero

Mutase

Phosphoglycerate mutase

10.2210/pdb5oaw/pdb

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Crystal structure of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei in complex with inhibitor

Wenxia Fang Olawale G. Raimi D.M.F. vanAalten

Uridine diphosphate

10.2210/pdb4bqh/pdb

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Effect of germination time on fat and protein contents, and α-amylase activity of Guinea Corn (Sorghum vulgare)

Olawale G. Raimi S.N. Olaitan O.O. Fajana J.O. Sanni

The effect of germination time on the malt quality of guinea corn was studied by germinating guinea corn for different period of time. Germination had a significant effect on α- amylase activity, fat and protein contents of guinea corn. The protein and fat contents of guinea corn decreased as germination time increases while the α- amylase activity increased as germination time increases. The fat content at day 1,3 5, and 7 was found to be 8.2%, 6.4%, 4.8% and 2.0% respectively. Protein content was also found to be 2.16%, 1.48%, 1.23% and 1.04% at the day 1, 3, 5 and 7 respectively while the α- amylase activity was found to be 1.88, 2.22, 3.22 and 4.44 µmole/min/ml at day 1, 3,5 and 7 respectively.

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A Novel Allosteric Inhibitor of the Uridine Diphosphate N-Acetylglucosamine Pyrophosphorylase from Trypanosoma brucei

ACS Chemical Biology (2013)

Michael D. Urbaniak Iain T. Collie Wenxia Fang Tonia Aristotelous Susanne Eskilsson

Uridine diphosphate N-acetylglucosamine pyrophosphorylase (UAP) catalyzes the final reaction in the biosynthesis of UDP-GlcNAc, an essential metabolite in many organisms including Trypanosoma brucei, the etiological agent of Human African Trypanosomiasis. High-throughput screening of recombinant T. brucei UAP identified a UTP-competitive inhibitor with selectivity over the human counterpart despite the high level of conservation of active site residues. Biophysical characterization of the UAP enzyme kinetics revealed that the human and trypanosome enzymes both display a strictly ordered bi–bi mechanism, but with the order of substrate binding reversed. Structural characterization of the T. brucei UAP–inhibitor complex revealed that the inhibitor binds at an allosteric site absent in the human homologue that prevents the conformational rearrangement required to bind UTP. The identification of a selective inhibitory allosteric binding site in the parasite enzyme has therapeutic potential.

Uridine diphosphate

Enzyme Kinetics

10.1021/cb400411x

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Recognition of a glycosylation substrate by the O-GlcNAc transferase TPR repeats

Open Biology (2017)

Karim Rafie Olawale G. Raimi Andrew T. Ferenbach Vladimir S. Borodkin Vaibhav Kapuria

O-linked N -acetylglucosamine (O-GlcNAc) is an essential and dynamic post-translational modification found on hundreds of nucleocytoplasmic proteins in metazoa. Although a single enzyme, O-GlcNAc transferase (OGT), generates the entire cytosolic O-GlcNAc proteome, it is not understood how it recognizes its protein substrates, targeting only a fraction of serines/threonines in the metazoan proteome for glycosylation. We describe a trapped complex of human OGT with the C-terminal domain of TAB1, a key innate immunity-signalling O-GlcNAc protein, revealing extensive interactions with the tetratricopeptide repeats of OGT. Confirmed by mutagenesis, this interaction suggests that glycosylation substrate specificity is achieved by recognition of a degenerate sequon in the active site combined with an extended conformation C-terminal of the O-GlcNAc target site.

Tetratricopeptide

Transferase

Proteome

10.1098/rsob.170078

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Citations (55)

Mapping of a N-terminal α-helix domain required for human PINK1 stabilisation, Serine228 autophosphorylation and activation in cells

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Poonam Kakade Hina Ojha Olawale G. Raimi Andrew M. Shaw Andrew D. Waddell

Abstract Human autosomal recessive mutations in the PINK1 gene are causal for Parkinson’s disease (PD). PINK1 encodes a mitochondrial localised protein kinase that is a master-regulator of mitochondrial quality control pathways. Structural studies to date have elaborated the mechanism of how mutations located within the kinase domain disrupt PINK1 function, however, the molecular mechanism of PINK1 mutations located upstream and downstream of the kinase domain are unknown. We have employed mutagenesis studies of human PINK1 in cells to define the minimal region of PINK1, required for optimal ubiquitin phosphorylation, beginning at residue Ile111. Bioinformatic analysis of the region spanning Ile111 to the kinase domain and inspection of the AlphaFold human PINK1 structure model predicts a conserved N-terminal α-helical domain extension (NTE domain) within this region corroborated by hydrogen/deuterium exchange mass spectrometry (HDX-MS) of recombinant insect PINK1 protein. The AlphaFold structure also predicts the NTE domain forms an intramolecular interaction with the C-terminal extension (CTE). Cell-based analysis of human PINK1 reveals that PD-associated mutations (e.g. Q126P), located within the NTE:CTE interface, markedly inhibit stabilization of PINK1; autophosphorylation at Serine228 (Ser228); and Ubiquitin Serine65 (Ser65) phosphorylation. Furthermore, we provide evidence that NTE domain mutants do not affect intrinsic catalytic kinase activity but do disrupt PINK1 stabilisation at the mitochondrial Translocase of outer membrane (TOM) complex. The clinical relevance of our findings is supported by the demonstration of defective stabilization and activation of endogenous PINK1 in human fibroblasts of a patient with early-onset PD due to homozygous PINK1 Q126P mutations. Overall, we define a functional role of the NTE:CTE interface towards PINK1 stabilisation and activation and show that loss of NTE:CTE interactions is a major mechanism of PINK1-associated mutations linked to PD.

PINK1

Protein kinase domain

10.1101/2021.09.06.459138

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Author response for "A Mechanism-inspired UDP-N-acetylglucosamine Pyrophosphorylase Inhibitor"

Olawale G. Raimi Ramón Hurtado‐Guerrero Vladimir S. Borodkin Andrew T. Ferenbach Michael D. Urbaniak

N-Acetylglucosamine

10.1039/c9cb00017h/v2/response1

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O-GlcNAc transferase from Drososphila melanogaster

Daniel Mariappa Xiaowei Zheng Marianne Schimpl Olawale G. Raimi Karim Rafie

Transferase

10.2210/pdb5a01/pdb

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N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Nature (2010)

Julie A. Frearson Stephen Brand Stuart P. McElroy Laura A. T. Cleghorn Ondřej Šmíd

Trypanocidal agent

Neglected Tropical Diseases

10.1038/nature08893

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Citations (288)

Genetic and structural validation of Aspergillus fumigatus N-acetylphosphoglucosamine mutase as an antifungal target

Bioscience Reports (2013)

Wenxia Fang Ting Du Olawale G. Raimi Ramón Hurtado‐Guerrero Karina V. Mariño

Aspergillus fumigatus is the causative agent of IA (invasive aspergillosis) in immunocompromised patients. It possesses a cell wall composed of chitin, glucan and galactomannan, polymeric carbohydrates synthesized by processive glycosyltransferases from intracellular sugar nucleotide donors. Here we demonstrate that A. fumigatus possesses an active AfAGM1 (A. fumigatus N-acetylphosphoglucosamine mutase), a key enzyme in the biosynthesis of UDP (uridine diphosphate)–GlcNAc (N-acetylglucosamine), the nucleotide sugar donor for chitin synthesis. A conditional agm1 mutant revealed the gene to be essential. Reduced expression of agm1 resulted in retarded cell growth and altered cell wall ultrastructure and composition. The crystal structure of AfAGM1 revealed an amino acid change in the active site compared with the human enzyme, which could be exploitable in the design of selective inhibitors. AfAGM1 inhibitors were discovered by high-throughput screening, inhibiting the enzyme with IC50s in the low μM range. Together, these data provide a platform for the future development of AfAGM1 inhibitors with antifungal activity.

Mutase

10.1042/bsr20130053

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Citations (26)