UCL Division of Biosciences

Prof Christopher Danpure

Prof Christopher Danpure

Emeritus Professor Molecular Cell Biology

Div of Biosciences

Faculty of Life Sciences

Joined UCL
1st Apr 2000

Research summary

For the past 20 years I have worked on various aspects of the variable peroxisomal and mitochondrial targeting of the intermediary metabolic enzyme alanine:glyoxylate aminotransferase (AGT) and its relationship to hereditary calcium oxalate kidney stone diseases. More specifically, my research has concentrated on two areas:- 1) the molecular basis for the episodic fluctuations in AGT targeting during mammalian evolution under the influence of dietary selection pressure; 2) the effect of mutations in AGT on its folding, dimerization, and intracellular compartmentalization, and the downstream effects of AGT dysfunction on oxalate synthesis in primary hyperoxaluria type 1 (PH1). My key achievements have been as follows:- 1986. Discovered basic enzyme defect in PH1 (i.e. AGT deficiency). 1986-7. Carried out the first enzyme prenatal and postnatal diagnoses of PH1. 1986. Provided rationale and support for first successful liver transplantation as a form of enzyme replacement therapy in PH1. 1989. Discovered AGT peroxisome-to-mitochondrion mistargeting in PH1. 1990. Cloned the human AGT gene. 1990. Identified first mutations in AGT in PH1, including the mutation-polymorphism combination responsible for AGT mistargeting. 1991. Mapped the chromosomal location and intron-exon boundaries of the human AGT gene (AGXT). 1992-4. Cloned and functionally characterized the marmoset, rabbit and cat AGT genes, and proposed the role of dietary selection pressure in determining the peroxisomal and/or mitochondrial compartmentalization of mammalian AGT. 1995. Functionally identified AGT as a PTS1 protein. 1996. Determined the mechanism of AGT mistargeting in PH1. 1998. Cloned and functionally characterized the guinea pig AGT gene. 2000. Demonstrated that the AGT gene in primates evolved under positive (dietary?) selection pressure. 2000. Demonstrated the functional synergism between the common Pro11Leu polymorphism and many PH1-specific mutations in AGT. 2000-5. Demonstrated the atypical nature of the AGT PTS1. 2003. Determined the crystal structure of human AGT. 2003. Demonstrated the normalization of mutant AGT targeting in vitro using protein stabilization agents. 2004. Demonstrated that the AGT gene in Carnivora evolved under positive (dietary?) selection pressure. 2004. Demonstrated that the human population distribution of the AGT Pro11Leu polymorphism is compatible with its frequency being influenced by ancestral dietary history. 2005. Provided the first statistical validation of the evolutionary relationship between diet and AGT compartmentalization in mammals. 2005. Identified the ancillary peroxisomal targeting information (PTS1A) in human AGT. 2006. Constructed a set of singly, doubly and triply-transformed CHO cells suitable for the high-throughput screening of chemical chaperones as potential pharmacological treatments for PH1. My current research concentrates on development cell-based model systems suitable for the high-throughput screening of protein stabilising agents with potential for the pharmacological treatment of primary hyperoxaluria.

Teaching summary

Course organizer for:- BIOL2014 Cell Biology (year 2), BIOL3006 Molecular Cell Biology (year 3/4). Lecturer on:- BIOL2014 Cell Biology (year 2), BIOL3006 Molecular Cell Biology (year 3/4), BIOL3010 Molecular Evolution (year 3), BIOL3013 Genes to Disease to Therapy (year 3), PHOL2007 Principles of Cellular Control (year 2).