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Instruments / Technical Area	Publication Details	Published
I18-Microfocus Spectroscopy	Microfocus x-ray fluorescence mapping of tumour penetration by an organo‑osmium anticancer complex Carlos Sanchez-cano , Isolda Romero-canelón , Kalotina Geraki , Peter Sadler Journal Of Inorganic Biochemistry DOI: 10.1016/j.jinorgbio.2018.04.014 Diamond Proposal Number(s): [13478] Open Access Show Abstract ▼ Abstract: Microfocus synchrotron x-ray fluorescence (SXRF) imaging focussed on detection of the Os LIII edge shows that the organo‑osmium metallodrug candidate [(ŋ6-p-cym)Os(Azpy-NMe2)I]+ (p-cym = p-cymene, Azpy-NMe2 = 2-(p-([dimethylamino]phenylazo)pyridine)) [1] penetrates efficiently into the interior of A2780 human ovarian cancer cell spheroids, a model for a solid tumour. The accompanying changes in Zn and Ca distribution suggest that the complex causes nuclear damage and initiates signalling events for cell death, consistent with findings for cultured cancer cell monolayers. Such tumour penetration is likely to be important for combatting resistance to chemotherapy, which is becoming a problem for current clinical platinum drugs.	Apr 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Structural and catalytic properties of the peroxygenase P450 enzyme CYP152K6 from Bacillus methanolicus Hazel M. Girvan , Harshwardhan Poddar , Kirsty J. Mclean , David R. Nelson , Katherine A. Hollywood , Colin W. Levy , David Leys , Andrew W. Munro Journal Of Inorganic Biochemistry DOI: 10.1016/j.jinorgbio.2018.08.002 Diamond Proposal Number(s): [17773] Open Access Show Abstract ▼ Abstract: The CYP152 family of cytochrome P450 enzymes (P450s or CYPs) is bacterial peroxygenases that use hydrogen peroxide to drive hydroxylation and decarboxylation of fatty acid substrates. We have expressed and purified a novel CYP152 family member – CYP152K6 from the methylotroph Bacillus methanolicus MGA3. CYP152A6 was characterized using spectroscopic, analytical and structural methods. CYP152A6, like its peroxygenase counterpart P450SPα (CYP152B1) from Sphingomonas paucimobilis, does not undergo significant fatty acid-induced perturbation to the heme spectrum, with the exception of a minor Soret shift observed on binding dodecanoic acid. However, CYP152K6 purified from an E. coli expression system was crystallized and its structure was determined to 1.3 Å with tetradecanoic acid bound. No lipids were present in conditions used for crystallogenesis, and thus CYP152K6 must form a complex by incorporating the fatty acid from E. coli cells. Turnover studies with dodecanoic acid revealed several products, with 2-hydroxydodecanoic acid as the major product and much smaller quantities of 3-hydroxydodecanoic acid. Secondary turnover products were undec-1-en-1-ol, 2-hydroxydodec-2-enoic acid and 2,3-dihydroxydodecanoic acid. This is the first report of a 2,3-hydroxylated fatty acid product made by a peroxygenase P450, with the dihydroxylated product formed by CYP152K6-catalyzed 3-hydroxylation of 2-hydroxydodecanoic acid, but not by 2-hydroxylation of 3-hydroxydodecanoic acid.	Aug 2018
I02-Macromolecular Crystallography	Use of ferrous iron by metallo-β-lactamases Samuel T. Cahill , Hanna Tarhonskaya , Anna M. Rydzik , Emily Flashman , Michael A. Mcdonough , Christopher J. Schofield , Jurgen Brem Journal Of Inorganic Biochemistry 163, 185 - 193 DOI: 10.1016/j.jinorgbio.2016.07.013 Open Access Show Abstract ▼ Abstract: Metallo-β-lactamases (MBLs) catalyse the hydrolysis of almost all β-lactam antibacterials including the latest generation carbapenems and are a growing worldwide clinical problem. It is proposed that MBLs employ one or two zinc ion cofactors in vivo. Isolated MBLs are reported to use transition metal ions other than zinc, including copper, cadmium and manganese, with iron ions being a notable exception. We report kinetic and biophysical studies with the di-iron(II)-substituted metallo-β-lactamase II from Bacillus cereus (di-Fe(II) BcII) and the clinically relevant B1 subclass Verona integron-encoded metallo-β-lactamase 2 (di-Fe(II) VIM-2). The results reveal that MBLs can employ ferrous iron in catalysis, but with altered kinetic and inhibition profiles compared to the zinc enzymes. A crystal structure of di-Fe(II) BcII reveals only small overall changes in the active site compared to the di-Zn(II) enzyme including retention of the di-metal bridging water; however, the positions of the metal ions are altered in the di-Fe(II) compared to the di-Zn(II) structure. Stopped-flow analyses reveal that the mechanism of nitrocefin hydrolysis by both di-Fe(II) BcII and di-Fe(II) VIM-2 is altered compared to the di-Zn(II) enzymes. Notably, given that the MBLs are the subject of current medicinal chemistry efforts, the results raise the possibility the Fe(II)-substituted MBLs may be of clinical relevance under conditions of low zinc availability, and reveal potential variation in inhibitor activity against the differently metallated MBLs.	Oct 2016

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