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CDB Seminars
Thursday 24 May at 1pm __________________________ Thursday 31st May at 1pm
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Professor Chris Danpure
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Chris
Danpure, PhD
FMedSci
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Academic Career
2008-present
Research
Department of Cell and Developmental Biology, UCL
1994-2008
Department
of Biology, UCL
1994-2001
MRC
Laboratory
for Molecular Cell Biology
1973-1994
MRC
Clinical
Research Centre, Harrow
1971-1973
Beecham
Research Laboratories, Harlow
1968-1971
PhD
(Biochemistry) Institute of Cancer Research, University of London
1965-1968
BSc
(Physiology
& Biochemistry) University of Reading
Research
The intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT) is unusual insofar as it can be targeted to different parts of the cell (i.e. peroxisomes and/or mitochondria) under different circumstances. Under the influence of dietary selection pressure, its subcellular distribution has changed on at least twenty occasions during the evolution of mammals. In extant species, AGT tends to be peroxisomal in herbivores, mitochondrial in carnivores, and both peroxisomal and mitochondrial in omnivores. AGT deficiency in humans leads to the autosomal recessive disorder primary hyperoxaluria type 1 (PH1), which is characterised by excessive synthesis and excretion of oxalate and the deposition of insoluble calcium oxalate in the kidney and urinary tract. In the largest single subset of patients, AGT is mistargeted from the peroxisomes to the mitochondria due to the synergistic interaction between a common polymorphism and a disease-specific mutation. Although still catalytically active, AGT is metabolically inefficient when mislocalized to human mitochondria.
Over the past fifteen years,
my laboratory has been interested in elucidating the molecular and cellular
bases of AGT targeting in both mammalian evolution and human hereditary disease.
We have been especially interested in the mutational events that lead to changes
in AGT targeting during mammalian evolution, as well as the molecular and
cellular nature of the atypical behaviour of the peroxisomal targeting sequence
in the human. In addition, we have been interested in elucidating the complex
genotype-phenotype relationships in PH1 and how this information might be used
in the development of new treatments. We have recently solved the crystal
structure of human AGT and are currently looking at the development of
targeting-based bioassays in order to test the effects of small molecules
(chemical chaperones) that might stabilise AGT and counteract the effects of
disease-causing mutations. Such drugs might have use not only for PH1, but also
for the much more common idiopathic calcium oxalate kidney stone diseases.
References
- Lumb, M.J., Birdsey, G.M. & Danpure, C.J. Correction of an enzyme trafficking defect in hereditary kidney stone disease in vitro. Biochem. J. 374, 79-87 (2003)
- Zhang, X, Roe, S.M., Hou, Y., Bartlam, M., Rao, Z., Pearl, L.H. & Danpure, C.J. Crystal structure of alanine:glyoxylate aminotransferase and the relationship between genotype and enzymatic phenotype in primary hyperoxaluria type 1. J. Mol. Biol. 331, 643-652 (2003)
- Danpure, C.J. & Rumsby, G. Molecular aetiology of primary hyperoxaluria and its implications for clinical management. Expert Rev. Mol. Med. 6, DOI: 10.1017/S1462399404007203 (2004)
- Birdsey, G.M., Lewin, J., Cunningham, A.A., Bruford, M.W. & Danpure, C.J. Differential enzyme targeting as an evolutionary adaptation to herbivory in Carnivora. Mol. Biol. Evol. 21, 632-646 (2004)
Page last modified on 24 may 10 15:33 by Glenda Young
