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Articles by Patrick Rabe
KDM3A catalyses the oxidation of acetyl-lysine to hydroxyacetyl-lysine on histone H3K9
Abstract Histone modifications, including Nε-lysine acetylation and methylation, play critical roles in the regulation of eukaryotic transcription. The addition of acetyl and methyl groups and removal of acetyl groups to histones involve redox-neutral reactions. Demethylation is O2-dependent, as reported for reactions catalysed by the 2-oxoglutarate-dependent hypoxia-inducible factor (HIF) hydroxylases, one of which is structurally related to the Jumonji-C (JmjC) histone demethylases.
Structural basis of the promiscuity of the unusual Fe(II) and 2-oxoglutarate dependent human aspartate/asparagine-β-hydroxylase - Nature Communications
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Abstract Protein-hydroxylation catalysed by Fe(II) and 2-oxoglutarate (2OG) dependent oxygenases is an important regulatory mechanism in human biology. Such oxygenases typically coordinate their Fe(II) cofactor via a conserved triad of an aspartate- or glutamate- and two histidine-residues.
By Mariska de Munnik, Amelia Brasnett, Tiankun Zhou, William Myers, Yicheng Wang, Kuntal Chatterjee, Anthony Tumber, Stephen Marshall, Philipp Simon, Pierre Aller, Danny Axford, Hiroki Makita, Daniel W. Paley, Vandana Tiwari, Sebastian Dehe, Humberto Sanchez, Daniel Rosenberg, Roberto Alonso-Mori, Asmit Bhowmick, Junko Yano, Vittal K. Yachandra, Jaehyun Park, Sehan Park, Allen M. Orville, Lennart Brewitz, Jan Kern, Christopher J Schofield, Patrick Rabe, Anastasiia Shilova, Alexander T. Stead
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Nature
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Structural and functional consequences of aspartate/asparagine-β-hydroxylase variants causing Traboulsi Syndrome
KEYWORDS Aspartate/asparagine-β-hydroxylase / AspH / BAH / HAAH 2-oxoglutarate / α-ketoglutarate oxygenase Traboulsi Syndrome epidermal growth factor-like domain rare disease Marfan Syndrome hypoxia dioxygenase post translational modification enzyme mutation ABBREVIATIONS AND NOMENCLATURE 2OA (2-Oxoadipate) 2OG (2-Oxoglutarate) 2OP (2-Oxopimelate) 2OS (2-Oxosuberate) FAS (Ammonium iron(II) sulfate hexahydrate) AspH (Aspartate/asparagine-β-hydroxylase) DURS1 (Duane Retraction Syndrome 1) EGFD...
Filamin C dimerisation is regulated by HSPB7 - Nature Communications
Abstract The biomechanical properties and responses of tissues underpin a variety important of physiological functions and pathologies. In striated muscle, the actin-binding protein filamin C (FLNC) is a key protein whose variants causative for a wide range of cardiomyopathies and musculoskeletal pathologies. FLNC is a multi-functional protein that interacts with a variety of partners, however, how it is regulated at the molecular level is not well understood.
Targeting Mycobacterial Transpeptidases: Evaluating the Roles of Ldt and PBP Inhibition in Suppressing Mycobacterium smegmatis
Abstract β-Lactams demonstrate promising in vitro activity against Mycobacterium species and are being explored for tuberculosis treatment; however, evidence of their in vivo efficacy versus Mycobacterium tuberculosis remains limited. To achieve broad clinically relevant potency, optimisation of the classical β-lactam scaffolds or development of new or non-β-lactam inhibitors for mycobacterial transpeptidases is likely required.
JmjC catalysed histone H2a N-methyl arginine demethylation and C4-arginine hydroxylation reveals importance of sequence-reactivity relationships - Communications Biology
Abstract 2-Oxoglutarate (2OG) dependent Nε-methyl lysine demethylases (JmjC-KDMs) regulate eukaryotic transcription. We report studies showing that isolated forms of all human KDM4 and KDM5 JmjC enzymes catalyse demethylation of N-methylated Arg-3 of histone H2a. Unexpectedly, the results reveal that KDM4E and, less efficiently, KDM4D catalyse C-4 hydroxylation of Arg-20 of H2a on peptides, recombinant H2a, and calf histone extracts, including when the Arg-20 guanidino group is N-methylated.
Biochemical and crystallographic studies of l,d-transpeptidase 2 from Mycobacterium tuberculosis with its natural monomer substrate - Communications Biology
Abstract The essential l,d-transpeptidase of Mycobacterium tuberculosis (LdtMt2) catalyses the formation of 3\(\to\)3 cross-links in cell wall peptidoglycan and is a target for development of antituberculosis therapeutics. Efforts to inhibit LdtMt2 have been hampered by lack of knowledge of how it binds its substrate.
Interactions of hydrolyzed β-lactams with the L1 metallo-β-lactamase: Crystallography supports stereoselective binding of cephem/carbapenem products
Introduction Antimicrobial resistance (AMR) is a growing health and economic threat and has been estimated to be directly responsible for 1.27 million deaths worldwide in 2019 ( 1 Antimicrobial Resistance C. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. ). β-Lactams are the most prescribed and the most clinically important antibiotics used to treat bacterial infections ( 2 beta-Lactams and beta-Lactamase Inhibitors: An Overview.
Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane - Nature
Abstract Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3.
Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors - Nature Communications
Abstract Ivosidenib, an inhibitor of isocitrate dehydrogenase 1 (IDH1) R132C and R132H variants, is approved for the treatment of acute myeloid leukaemia (AML). Resistance to ivosidenib due to a second site mutation of IDH1 R132C, leading to IDH1 R132C/S280F, has emerged.
Spectroscopic studies reveal details of substrate-induced conformational changes distant from the active site in isopenicillin N synthase
Introduction Members of the 2-oxoglutarate (2OG) oxygenase structural superfamily are widespread in nature and have important roles, including in collagen biosynthesis, lipid metabolism, nucleic acid repair, signalling, and antibiotic biosynthesis.( 1 Rabe P. Kamps J.J.A.G. Schofield C.J. Lohans C.T. Roles of 2-oxoglutarate oxygenases and isopenicillin N synthase in β-lactam biosynthesis. , 2 Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases. , 3 Schofield, C.
X-ray free-electron laser studies reveal correlated motion during isopenicillin N synthase catalysis
Abstract Isopenicillin N synthase (IPNS) catalyzes the unique reaction of l-δ-(α-aminoadipoyl)-l-cysteinyl-d-valine (ACV) with dioxygen giving isopenicillin N (IPN), the precursor of all natural penicillins and cephalosporins.
Two Diterpene Synthases for Spiroalbatene and Cembrene A from Allokutzneria albata
Two bacterial diterpene synthases from the actinomycete Allokutzneria albata were investigated, resulting in the identification of the structurally unprecedented compound spiroalbatene from the first and cembrene A from the second enzyme. Both enzymes were deeply investigated for their mechanisms by isotopic labelling experiments, site-directed mutagenesis, and variation of metal cofactors and pH.
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