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Coenzyme A pathway

We have a long term interest in the enzymology of Coenzyme A, both the pathway up to pantothenate (vitamin B5) (present in plants, microorganisms and fungi) and the pathway from pantothenate to Coenzyme A (present in all cells) [Nat. Prod. Rep. 2004]. Our research in this area is in collaboration with Professor Alison Smith (Plant Sciences) and Professor Tom Blundell (Biochemistry).

We have a specific interest in targeting the coenzyme A pathway enzymes from Mycobacterium tuberculosis. We are using a range of biophysical techniques including thermal shift, NMR spectroscopy, ITC and X-ray crystallography to identify molecular fragments that bind to these enzymes. These fragments act as starting points for elaboration to potent enzyme inhibitors (see section on Fragment-based approaches to enzyme inhibitors).

We described a fragment-based approach to the development of inhibitors of M. tuberculosis pantothenate synthetase, using fragment linking and fragment growing strategies [Angew. Chemie Intl. Ed. 2009] and exploration of group efficiencies [ChemMedChem, 2016].

Two fragments millimolar affinity Micromolar inhibitor
Cross section of active site of M. tuberculosis pantothenate synthetase with two fragments bound (millimolar affinity), and with micromolar inhibitor made by linking them.
[ChemMedChem, 2016]

Related Publications

   Optimization of inhibitors of Mycobacterium tuberculosis pantothenate synthetase based on group efficiency analysis
A W Hung, H L Silvestre, S Wen, G P George, J Boland, T L Blundell, A Ciulli, C Abell
ChemMedChem, 2015
DOI: 10.1002/cmdc.201500414
   Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery
H L Silvestre, T L Blundell, C Abell, A Ciulli
Proc. Natl. Acad. Sci. U.S.A, 2013, 110, 12984-9
DOI: 10.1073/pnas.1304045110
   Optimisation of the interligand Overhauser effect for fragment linking: application to inhibitor discovery against Mycobacterium tuberculosis pantothenate synthetase.
P Sledź, H L Silvestre, A W Hung, A Ciulli, T L Blundell & C Abell
J. Am. Chem. Soc. 2010, 132, 4544-4545.
DOI: 10.1021/ja100595u
   Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase.
A W Hung, H L Silvestre, S Wen, A Ciulli, T L Blundell & C Abell
Angew. Chemie Intl. Ed. 2009, 48, 8452-8456.

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