Dr David Miller
(e/fe)

MA (Oxon), PhD, MRSC

Uwch Ddarlithydd mewn Cemeg Fiolegol a Chyfarwyddwr Rhaglenni Ôl-raddedig a Addysgir (PGT)

Mae gen i ddiddordeb yn y defnydd o gemeg organig synthetig fel y'i cymhwysir i ddatrys problemau biolegol ac i'r gwrthwyneb. Yn aml, gellir ymchwilio i'r ddealltwriaeth o sut mae macromolecwlau natur fel proteinau a DNA yn gweithio a rhyngweithio â'i gilydd trwy ddefnyddio moleciwlau organig bach. Yn aml, nid yw moleciwlau o'r fath ar gael o'r pwll naturiol ac felly mae'r cemegydd synthetig yn ganolog i ddatrys problemau o'r fath. Yn yr un modd, gall cemeg synthetig er ei bod yn gallu paratoi'r moleciwlau mwyaf cymhleth a chymhleth yn aml ond wneud hynny ar draul fawr o amser ac adnoddau. Mae systemau naturiol, os cânt eu harneisio'n gywir yn cynnig cyfle i adeiladu moleciwlau o gymhlethdod o'r fath yn llawer cyflymach ac yn fwy effeithlon.

Rwy'n cynnig prosiectau BSc mewn ymchwil addysg.

Date
Type

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 25(23), 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 -London- 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 451(3), pp. 417-426. (10.1042/BJ20130041)

2012

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)
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)
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)
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)
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)

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)

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$acirc; 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.

Diagram showing the natural substrate inositol-1-phosphate bound at the active site of IMPase.

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.

Mercaptoacrylate PD150606 bound to domain VI of calpain.

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.

Diagram showing the sesquiterpene precursor farnesyl diphosphate and some of the downstream sesquiterpene products.

CH5103 Sylfeini Cemeg Organig

CH5130 Cyflwyniad i Ddatblygu Cyffuriau

CH3317 Biosynthesis Peirianneg

Prosiect Ymchwil CHT008

CHT214 Biocatalysis I: Dulliau Modern o Fiocatalysis

Sgiliau Allweddol CHT232

CHT223 Biocatalysis II: Cymwysiadau Diwydiannol Biocatalysis

CHT550 a CHT555 Cymhwyso dulliau ymchwil.

CHT327 Biosynthesis Peirianneg

Gellir dod o hyd i fanylion am fodiwlau yma.

MA mewn Cemeg gyda Chemeg Cwantwm Atodol, Coleg Oriel Rhydychen, 1989-1993.

PhD, Prifysgol Southampton (dan yr Athro T. D. H. Bugg) 1993-1997.

Cynorthwy-ydd Ymchwil Ôl-ddoethurol, Prifysgol St Andrews 1997-1998.

Cynorthwy-ydd Ymchwil Ôl-ddoethurol, Prifysgol Birmingham 1998-2005.

Cymrawd Ymchwil Ôl-ddoethurol, Prifysgol Caerdydd 2005-2007.

Cynorthwy-ydd Ymchwil yn 2007.

Darlithydd 2015-2022.

Uwch Ddarlithydd 2022.

Aelodaethau proffesiynol

Aelod o'r Gymdeithas Frenhinol Cemeg

Contact Details

MillerDJ@caerdydd.ac.uk
+44 29208 74068

Themâu ymchwil

Arbenigeddau

Biosynthesis
cemeg fiolegol
Cemeg organig
Pheromones a Semiochemicals eraill
Biocatalysis a thechnoleg ensym