Dr David Miller
Senior Lecturer in Biological Chemistry and Director of Post Graduate Taught (PGT) Programmes
Overview
I am interested in the use of synthetic organic chemistry as applied to the solution of biological problems and vice versa. The understanding of how Nature's macromolecules such as proteins and DNA work and interact with one another can often be probed by use of small organic molecules. Such molecules are often not available from the natural pool and so the synthetic chemist is central to solving such problems. Similarly, synthetic chemistry although well capable of preparing the most complex and intricate of molecules can often only do so at great expense of time and resources. Natural systems, if harnessed correctly offer the opportunity to construct molecules of such complexity much more quickly and efficiently.
Publication
2024
- González Requena, V., Srivastava, P. L., Miller, D. J. and Allemann, R. K. 2024. Single point mutation abolishes water capture in germacradien‐4‐ol synthase. ChemBioChem, article number: e202400290. (10.1002/cbic.202400290)
- Srivastava, P. L. et al. 2024. Simulation-guided engineering enables a functional switch in selinadiene synthase toward hydroxylation. ACS Catalysis 14(14), pp. 11034–11043. (10.1021/acscatal.4c02032)
- Srivastava, P. L., Johnson, L. A., Miller, D. J. and Allemann, R. K. 2024. Production of non-natural terpenoids through chemoenzymatic synthesis using substrate analogs. In: Methods in Enzymology. Elsevier, (10.1016/bs.mie.2024.03.015)
2023
- Srivastava, P., Johns, S. T., Walters, R., Miller, D. J., Van der Kamp, M. W. and Allemann, R. K. 2023. Active site loop engineering abolishes water capture in hydroxylating sesquiterpene synthases. ACS Catalysis 13(21), pp. 14199-14204. (10.1021/acscatal.3c03920)
2021
- Srivastava, P. L., Escorcia, A. M., Huynh, F., Miller, D. J., Allemann, R. K. and van der Kamp, M. W. 2021. Redesigning the molecular choreography to prevent hydroxylation in Germacradien-11-ol synthase catalysis. ACS Catalysis 11(3), pp. 1033–1041. (10.1021/acscatal.0c04647)
2020
- Cresser-Brown, J., Rizkallah, P., Jin, Y., Roth, C., Miller, D. J. and Allemann, R. K. 2020. An unexpected co-crystal structure of the calpain PEF(S) domain with Hfq reveals a potential chaperone function of Hfq. Acta Crystallographica Section F: Structural Biology Communications 76(2), pp. 81-85. (10.1107/S2053230X20001181)
2019
- Demiray, M., Miller, D. J. and Allemann, R. K. 2019. Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids. Beilstein Journal of Organic Chemistry 15, pp. 2184-2190. (10.3762/bjoc.15.215)
- Loizzi, M., Miller, D. J. and Allemann, R. K. 2019. Silent catalytic promiscuity in the high-fidelity terpene cyclase δ-cadinene synthase. Organic & Biomolecular Chemistry 17(5), pp. 1206-1214. (10.1039/C8OB02821D)
2018
- Kalash, L. et al. 2018. Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space. European Journal of Medicinal Chemistry 157, pp. 1264-1275. (10.1016/j.ejmech.2018.08.049)
- Huynh, F., Grundy, D. J., Jenkins, R. L., Miller, D. J. and Allemann, R. K. 2018. Sesquiterpene synthase-catalysed formation of a new medium-sized cyclic terpenoid ether from farnesyl diphosphate analogues. Chembiochem 19(17), pp. 1834-1838. (10.1002/cbic.201800218)
- Loizzi, M., Gonzalez Gonzalez, V., Miller, D. J. and Allemann, R. K. 2018. Nucleophilic water capture or proton loss: single amino acid switch converts δ-Cadinene synthase into germacradien-4-ol synthase. Chembiochem 19(1), pp. 100-105. (10.1002/cbic.201700531)
- Yaldizli, ?. et al. 2018. Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. Multiple Sclerosis and Related Disorders 19, pp. 168-170. (10.1016/j.msard.2016.08.006)
2015
- Adams, S., Robinson, E., Miller, D. J., Rizkallah, P., Hallett, M. B. and Allemann, R. K. 2015. Conformationally restricted calpain inhibitors. Chemical Science 6(12), pp. 6865-6871. (10.1039/c5sc01158b)
- Touchet, S., Chamberlain, K., Woodcock, C. M., Miller, D. J., Birkett, M. A., Pickett, J. A. and Allemann, R. K. 2015. Novel olfactory ligands via terpene synthases. Chemical Communications 51(35), pp. 7550-7553. (10.1039/C5CC01814E)
2014
- Adams, S. E., Rizkallah, P., Miller, D. J., Robinson, E. J., Hallett, M. B. and Allemann, R. K. 2014. The structural basis of differential inhibition of human calpain by indole and phenyl α--mercaptoacrylic acids. Journal of Structural Biology 187(3), pp. 236-241. (10.1016/j.jsb.2014.07.004)
2013
- Miller, D. J., Adams, S. E., Hallett, M. B. and Allemann, R. K. 2013. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future?. Future Medicinal Chemistry 5(17), pp. 2057-2074. (10.4155/fmc.13.172)
- Li, J. et al. 2013. Rational engineering of plasticity residues of sesquiterpene synthases from 'Artemisia annua': Product specificity and catalytic efficiency. Biochemical Journal 451(3), pp. 417-426. (10.1042/BJ20130041)
- Li, J. et al. 2013. Rational engineering of plasticity residues of sesquiterpene synthases from Artemisia annua: product specificity and catalytic efficiency. Biochemical Journal -London- 451(3), pp. 417-426. (10.1042/BJ20130041)
2012
- Miller, D. J. and Allemann, R. K. 2012. Sesquiterpene synthases: Passive catalysts or active players?. Natural Product Reports 29(1), pp. 60-71. (10.1039/c1np00060h)
- Faraldos, J. A., Miller, D. J., Gonzalez, V., Yoosuf-Aly, F. Z., Cascón, O., Li, A. and Allemann, R. K. 2012. A 1,6-ring closure mechanism for (+)-δ-cadinene synthase?. Journal of the American Chemical Society 134(13), pp. 5900-5908. (10.1021/ja211820p)
- Adams, S. E., Parr, C., Miller, D. J., Allemann, R. K. and Hallett, M. B. 2012. Potent inhibition of Ca2+-dependent activation of calpain-1 by novel mercaptoacrylates. MedChemComm 3(5), pp. 566-570. (10.1039/c2md00280a)
- Yoosuf-Aly, Z., Faraldos, J. A., Miller, D. J. and Allemann, R. K. 2012. Chemoenzymatic synthesis of the alarm pheromone (+)-verbenone from geranyl diphosphate. Chemical Communications 48, pp. 7040-7042. (10.1039/c2cc32883f)
- Cascón, O., Touchet, S., Miller, D. J., Gonzalez, V., Faraldos, J. A. and Allemann, R. K. 2012. Chemoenzymatic preparation of germacrene analogues. Chemical Communications 48(78), pp. 9702-9704. (10.1039/c2cc35542f)
2009
- Gennadios, H. A. et al. 2009. Crystal structure of (+)-δ-cadinene synthase from Gossypium arboreum and evolutionary divergence of metal binding motifs for catalysis. Biochemistry 48(26), pp. 6175-6183. (10.1021/bi900483b)
- Miller, D. J., Yu, F., Knight, D. W. and Allemann, R. K. 2009. 6- and 14-Fluoro farnesyl diphosphate: mechanistic probes for the reaction catalysed by aristolochene synthase. Organic & Biomolecular Chemistry 7(5), pp. 962-975. (10.1039/b817194g)
2008
- Miller, D. J., Yu, F. and Allemann, R. K. 2008. FLUO 14-Study of sesquiterpene cyclization reactions using fluorinated farnesyl diphosphate analogs. Abstracts of Papers of the American Chemical Society 236
- Shishova, E. Y. et al. 2008. X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis. Journal of Biological Chemistry 283(22), pp. 15431-15439. (10.1074/jbc.M800659200)
- Miller, D. J., Gao, J., Truhlar, D. G., Young, N. J., Gonzalez, V. and Allemann, R. K. 2008. Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti. Organic & Biomolecular Chemistry 6(13), pp. 2346-2354. (10.1039/b804198a)
2007
- Yu, F., Miller, D. J. and Allemann, R. K. 2007. Probing the reaction mechanism of aristolochene synthase with 12,13-difluorofarnesyl diphosphate. Chemical Communications- Royal Society of Chemistry(40), pp. 4155-4157. (10.1039/b709562g)
- Miller, D. J., Yu, F. and Allemann, R. K. 2007. Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. Chembiochem 8(15), pp. 1819-1825. (10.1002/cbic.200700219)
- Miller, D. J., Yu, F., Young, N. J. and Allemann, R. K. 2007. Competitive inhibition of aristolochene synthase by phenyl-substituted farnesyl diphosphates: evidence of active site plasticity. Organic & Biomolecular Chemistry 5(20), pp. 3287-3298. (10.1039/b713301b)
2006
- Nicoll, A. J., Miller, D. J., Fütterer, K., Ravelli, R. and Allemann, R. K. 2006. Designed high affinity Cu2+ -Binding α-Helical foldamer. Journal of the American Chemical Society 128(28), pp. 9187-9193. (10.1021/ja061513u)
2004
- Miller, D. J., Bashir-Uddin Surfraz, M., Akhtar, M., Gani, D. and Allemann, R. K. 2004. Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity. Organic & Biomolecular Chemistry 2(5), pp. 671-688. (10.1039/b312808c)
2003
- Bashir-Uddin Surfraz, M., Miller, D. J., Gani, D. and Allemann, R. K. 2003. Product-like inhibitors of inositol monophosphatase. Tetrahedron Letters 44(41), pp. 7677-7679. (10.1016/S0040-4039(03)01878-1)
1998
- Andersen, J. M., Karodia, N., Miller, D. J., Stones, D. and Gani, D. 1998. Preparation and catalytic properties of resin bound binuclear rhodium tetracarboxylate complexes. Tetrahedron Letters 39(42), pp. 7815-7818. (10.1016/S0040-4039(98)01709-2)
- Stones, D., Miller, D. J., Beaton, M. W., Rutherford, T. J. and Gani, D. 1998. A method for the quantification of resin loading using 19F gel phase NMR spectroscopy and a new method for benzyl ether linker cleavage in solid phase chemistry. Tetrahedron Letters 39(27), pp. 4875-4878. (10.1016/S0040-4039(98)00883-1)
- Miller, D. J., Hammond, S. M., Anderluzzi, D. and Bugg, T. D. H. 1998. Aminoalkylphosphinate inhibitors of D-Ala-D-Ala adding enzyme. Journal of the Chemical Society, Perkin Transactions 1(1), pp. 131-132. (10.1039/a704097k)
Articles
- González Requena, V., Srivastava, P. L., Miller, D. J. and Allemann, R. K. 2024. Single point mutation abolishes water capture in germacradien‐4‐ol synthase. ChemBioChem, article number: e202400290. (10.1002/cbic.202400290)
- Srivastava, P. L. et al. 2024. Simulation-guided engineering enables a functional switch in selinadiene synthase toward hydroxylation. ACS Catalysis 14(14), pp. 11034–11043. (10.1021/acscatal.4c02032)
- Srivastava, P., Johns, S. T., Walters, R., Miller, D. J., Van der Kamp, M. W. and Allemann, R. K. 2023. Active site loop engineering abolishes water capture in hydroxylating sesquiterpene synthases. ACS Catalysis 13(21), pp. 14199-14204. (10.1021/acscatal.3c03920)
- Srivastava, P. L., Escorcia, A. M., Huynh, F., Miller, D. J., Allemann, R. K. and van der Kamp, M. W. 2021. Redesigning the molecular choreography to prevent hydroxylation in Germacradien-11-ol synthase catalysis. ACS Catalysis 11(3), pp. 1033–1041. (10.1021/acscatal.0c04647)
- Cresser-Brown, J., Rizkallah, P., Jin, Y., Roth, C., Miller, D. J. and Allemann, R. K. 2020. An unexpected co-crystal structure of the calpain PEF(S) domain with Hfq reveals a potential chaperone function of Hfq. Acta Crystallographica Section F: Structural Biology Communications 76(2), pp. 81-85. (10.1107/S2053230X20001181)
- Demiray, M., Miller, D. J. and Allemann, R. K. 2019. Harnessing enzyme plasticity for the synthesis of oxygenated sesquiterpenoids. Beilstein Journal of Organic Chemistry 15, pp. 2184-2190. (10.3762/bjoc.15.215)
- Loizzi, M., Miller, D. J. and Allemann, R. K. 2019. Silent catalytic promiscuity in the high-fidelity terpene cyclase δ-cadinene synthase. Organic & Biomolecular Chemistry 17(5), pp. 1206-1214. (10.1039/C8OB02821D)
- Kalash, L. et al. 2018. Structure-based design of allosteric calpain-1 inhibitors populating a novel bioactivity space. European Journal of Medicinal Chemistry 157, pp. 1264-1275. (10.1016/j.ejmech.2018.08.049)
- Huynh, F., Grundy, D. J., Jenkins, R. L., Miller, D. J. and Allemann, R. K. 2018. Sesquiterpene synthase-catalysed formation of a new medium-sized cyclic terpenoid ether from farnesyl diphosphate analogues. Chembiochem 19(17), pp. 1834-1838. (10.1002/cbic.201800218)
- Loizzi, M., Gonzalez Gonzalez, V., Miller, D. J. and Allemann, R. K. 2018. Nucleophilic water capture or proton loss: single amino acid switch converts δ-Cadinene synthase into germacradien-4-ol synthase. Chembiochem 19(1), pp. 100-105. (10.1002/cbic.201700531)
- Yaldizli, ?. et al. 2018. Response to the commentary of Yates RL and DeLuca GC on the study: HLA-DRB1*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis. Multiple Sclerosis and Related Disorders 19, pp. 168-170. (10.1016/j.msard.2016.08.006)
- Adams, S., Robinson, E., Miller, D. J., Rizkallah, P., Hallett, M. B. and Allemann, R. K. 2015. Conformationally restricted calpain inhibitors. Chemical Science 6(12), pp. 6865-6871. (10.1039/c5sc01158b)
- Touchet, S., Chamberlain, K., Woodcock, C. M., Miller, D. J., Birkett, M. A., Pickett, J. A. and Allemann, R. K. 2015. Novel olfactory ligands via terpene synthases. Chemical Communications 51(35), pp. 7550-7553. (10.1039/C5CC01814E)
- Adams, S. E., Rizkallah, P., Miller, D. J., Robinson, E. J., Hallett, M. B. and Allemann, R. K. 2014. The structural basis of differential inhibition of human calpain by indole and phenyl α--mercaptoacrylic acids. Journal of Structural Biology 187(3), pp. 236-241. (10.1016/j.jsb.2014.07.004)
- Miller, D. J., Adams, S. E., Hallett, M. B. and Allemann, R. K. 2013. Calpain-1 inhibitors for selective treatment of rheumatoid arthritis: what is the future?. Future Medicinal Chemistry 5(17), pp. 2057-2074. (10.4155/fmc.13.172)
- Li, J. et al. 2013. Rational engineering of plasticity residues of sesquiterpene synthases from 'Artemisia annua': Product specificity and catalytic efficiency. Biochemical Journal 451(3), pp. 417-426. (10.1042/BJ20130041)
- Li, J. et al. 2013. Rational engineering of plasticity residues of sesquiterpene synthases from Artemisia annua: product specificity and catalytic efficiency. Biochemical Journal -London- 451(3), pp. 417-426. (10.1042/BJ20130041)
- Miller, D. J. and Allemann, R. K. 2012. Sesquiterpene synthases: Passive catalysts or active players?. Natural Product Reports 29(1), pp. 60-71. (10.1039/c1np00060h)
- Faraldos, J. A., Miller, D. J., Gonzalez, V., Yoosuf-Aly, F. Z., Cascón, O., Li, A. and Allemann, R. K. 2012. A 1,6-ring closure mechanism for (+)-δ-cadinene synthase?. Journal of the American Chemical Society 134(13), pp. 5900-5908. (10.1021/ja211820p)
- Adams, S. E., Parr, C., Miller, D. J., Allemann, R. K. and Hallett, M. B. 2012. Potent inhibition of Ca2+-dependent activation of calpain-1 by novel mercaptoacrylates. MedChemComm 3(5), pp. 566-570. (10.1039/c2md00280a)
- Yoosuf-Aly, Z., Faraldos, J. A., Miller, D. J. and Allemann, R. K. 2012. Chemoenzymatic synthesis of the alarm pheromone (+)-verbenone from geranyl diphosphate. Chemical Communications 48, pp. 7040-7042. (10.1039/c2cc32883f)
- Cascón, O., Touchet, S., Miller, D. J., Gonzalez, V., Faraldos, J. A. and Allemann, R. K. 2012. Chemoenzymatic preparation of germacrene analogues. Chemical Communications 48(78), pp. 9702-9704. (10.1039/c2cc35542f)
- Gennadios, H. A. et al. 2009. Crystal structure of (+)-δ-cadinene synthase from Gossypium arboreum and evolutionary divergence of metal binding motifs for catalysis. Biochemistry 48(26), pp. 6175-6183. (10.1021/bi900483b)
- Miller, D. J., Yu, F., Knight, D. W. and Allemann, R. K. 2009. 6- and 14-Fluoro farnesyl diphosphate: mechanistic probes for the reaction catalysed by aristolochene synthase. Organic & Biomolecular Chemistry 7(5), pp. 962-975. (10.1039/b817194g)
- Miller, D. J., Yu, F. and Allemann, R. K. 2008. FLUO 14-Study of sesquiterpene cyclization reactions using fluorinated farnesyl diphosphate analogs. Abstracts of Papers of the American Chemical Society 236
- Shishova, E. Y. et al. 2008. X-ray crystallographic studies of substrate binding to aristolochene synthase suggest a metal ion binding sequence for catalysis. Journal of Biological Chemistry 283(22), pp. 15431-15439. (10.1074/jbc.M800659200)
- Miller, D. J., Gao, J., Truhlar, D. G., Young, N. J., Gonzalez, V. and Allemann, R. K. 2008. Stereochemistry of eudesmane cation formation during catalysis by aristolochene synthase from Penicillium roqueforti. Organic & Biomolecular Chemistry 6(13), pp. 2346-2354. (10.1039/b804198a)
- Yu, F., Miller, D. J. and Allemann, R. K. 2007. Probing the reaction mechanism of aristolochene synthase with 12,13-difluorofarnesyl diphosphate. Chemical Communications- Royal Society of Chemistry(40), pp. 4155-4157. (10.1039/b709562g)
- Miller, D. J., Yu, F. and Allemann, R. K. 2007. Aristolochene synthase-catalyzed cyclization of 2-fluorofarnesyl-diphosphate to 2-fluorogermacrene A. Chembiochem 8(15), pp. 1819-1825. (10.1002/cbic.200700219)
- Miller, D. J., Yu, F., Young, N. J. and Allemann, R. K. 2007. Competitive inhibition of aristolochene synthase by phenyl-substituted farnesyl diphosphates: evidence of active site plasticity. Organic & Biomolecular Chemistry 5(20), pp. 3287-3298. (10.1039/b713301b)
- Nicoll, A. J., Miller, D. J., Fütterer, K., Ravelli, R. and Allemann, R. K. 2006. Designed high affinity Cu2+ -Binding α-Helical foldamer. Journal of the American Chemical Society 128(28), pp. 9187-9193. (10.1021/ja061513u)
- Miller, D. J., Bashir-Uddin Surfraz, M., Akhtar, M., Gani, D. and Allemann, R. K. 2004. Removal of the phosphate group in mechanism-based inhibitors of inositol monophosphatase leads to unusual inhibitory activity. Organic & Biomolecular Chemistry 2(5), pp. 671-688. (10.1039/b312808c)
- Bashir-Uddin Surfraz, M., Miller, D. J., Gani, D. and Allemann, R. K. 2003. Product-like inhibitors of inositol monophosphatase. Tetrahedron Letters 44(41), pp. 7677-7679. (10.1016/S0040-4039(03)01878-1)
- Andersen, J. M., Karodia, N., Miller, D. J., Stones, D. and Gani, D. 1998. Preparation and catalytic properties of resin bound binuclear rhodium tetracarboxylate complexes. Tetrahedron Letters 39(42), pp. 7815-7818. (10.1016/S0040-4039(98)01709-2)
- Stones, D., Miller, D. J., Beaton, M. W., Rutherford, T. J. and Gani, D. 1998. A method for the quantification of resin loading using 19F gel phase NMR spectroscopy and a new method for benzyl ether linker cleavage in solid phase chemistry. Tetrahedron Letters 39(27), pp. 4875-4878. (10.1016/S0040-4039(98)00883-1)
- Miller, D. J., Hammond, S. M., Anderluzzi, D. and Bugg, T. D. H. 1998. Aminoalkylphosphinate inhibitors of D-Ala-D-Ala adding enzyme. Journal of the Chemical Society, Perkin Transactions 1(1), pp. 131-132. (10.1039/a704097k)
Book sections
- Srivastava, P. L., Johnson, L. A., Miller, D. J. and Allemann, R. K. 2024. Production of non-natural terpenoids through chemoenzymatic synthesis using substrate analogs. In: Methods in Enzymology. Elsevier, (10.1016/bs.mie.2024.03.015)
Research
I am interested in the use of synthetic organic chemistry as applied to the solution of biological problems and vice versa. The understanding of how Nature's macromolecules such as proteins and DNA work and interact with one another can often be probed by use of small organic molecules. Such molecules are often not available from the natural pool and so the synthetic chemist is central to solving such problems. Similarly, synthetic chemistry although well capable of preparing the most complex and intricate of molecules can often only do so at great expense of time and resources. Natural systems, if harnessed correctly offer the opportunity to construct molecules of such complexity much more quickly and efficiently.
Inositol monophoshphatase.
Inositol monophosphatase is an enzyme that is involved in a crucial signal transduction pathway within our cells that has been implicated as a target for drugs that treat bipolar disorders. We are interested in the study of the mechanism of action of this enzyme and in the discovery of new inhibitors that may ultimately lead to better treatments for this debilitating condition.
mu-Calpain
Calpains are cysteine proteases that are activated by calcium ions. mu-Calpain is a member of this family of enzymes that appears to have a key role in cell-membrane expansion and hence motility of white blood cells (neutrophils). Development of potent and selective mu-calpain inhibitors may lead to a treatment for a variety of autoimmune diseases such as osteoarthritis.
Biosynthesis of terpenoids
Terpenes are the largest and most diverse group of natural products but originate from only a tiny group of prenyl diphosphate precursors. Diversity is generated in nature by the structurally similar terpene cyclases that form many different products from each prenyl diphosphate. By a combination of chemical synthesis, enzymology and molecular biology we seek to understand how such diversity can be created by enzymes that share a common fold.
Teaching
CH3216 Chemical Biology II: Introduction to Enzyme and Nucleic Acid Chemistry
CH3408 Modern Catalytic Processes
CHT008 Research Project
CHT214 Biocatalysis I: Modern Approaches to Biocatalysis
CHT215 Key Skills in Catalysis
CHT223 Biocatalysis II: Industrial Applications of Biocatalysis
CHT224 Medicinal Chemistry
CHT225 Practical Catalytic Chemistry
CHT401 Advanced Heterogeneous Catalysis
Biography
PhD, Southampton University (under Prof. T. D. H. Bugg). Postdoctoral research Fellow, University of St. Andrews 1997-1998. Post doctoral research fellow, Birmingham University 1998-2005. Post doctoral research fellow, Cardiff University 2005-2007. Appointed research fellow, 2007.