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Dive into the research topics where Graeme M. Birdsey is active.

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Featured researches published by Graeme M. Birdsey.


Biochemical and Biophysical Research Communications | 2003

Dimethylarginine dimethylaminohydrolase activity modulates ADMA levels, VEGF expression, and cell phenotype

Caroline L. Smith; Graeme M. Birdsey; Shelagh Anthony; Francesca Arrigoni; James Leiper; Patrick Vallance

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and is metabolised by dimethylarginine dimethylaminohydrolase (DDAH). Elevated levels of circulating ADMA correlate with various cardiovascular pathologies less is known about the cellular effects of altered DDAH activity. We modified DDAH activity in cells and measured the changes in ADMA levels, morphological phenotypes on Matrigel, and expression of vascular endothelial growth factor (VEGF). DDAH over-expressing ECV304 cells secreted less ADMA and when grown on Matrigel had enhanced tube formation compared to untransfected cells. VEGF mRNA levels were 2.1-fold higher in both ECV304 and murine endothelial cells (sEnd.1) over-expressing DDAH. In addition the DDAH inhibitor, S-2-amino-4(3-methylguanidino)butanoic acid (4124W 1mM), markedly reduced human umbilical vein endothelial cell tube formation in vitro. We have found that upregulating DDAH activity lowers ADMA levels, increases the levels of VEGF mRNA in endothelial cells, and enhances tube formation in an in vitro model, whilst blockade of DDAH reduces tube formation.


Biochemical Journal | 2003

Correction of an enzyme trafficking defect in hereditary kidney stone disease in vitro

Michael J. Lumb; Graeme M. Birdsey; Christopher J. Danpure

In normal human hepatocytes, the intermediary-metabolic enzyme alanine:glyoxylate aminotransferase (AGT) is located within the peroxisomes. However, in approx. one-third of patients suffering from the hereditary kidney stone disease primary hyperoxaluria type 1, AGT is mistargeted to the mitochondria. AGT mistargeting results from the synergistic interaction between a common P11L (Pro11-->Leu) polymorphism and a disease-specific G170R mutation. The polymorphism generates a functionally weak mitochondrial targeting sequence, the efficiency of which is increased by the mutation. The two substitutions together, but not in isolation, inhibit AGT dimerization, highlighting the different structural requirements of the peroxisomal and mitochondrial protein-import machineries. In the present study, we show that treatments known to increase the stability of proteins non-specifically (i.e. lowering the temperature from 37 to 30 degrees C or by the addition of glycerol) completely normalize the intracellular targeting of mutant AGT expressed in transfected COS cells. On the other hand, treatments known to decrease protein stability (e.g. increasing the temperature from 37 to 42 degrees C) exacerbate the targeting defect. Neither of the treatments affects the relative efficiencies of the peroxisomal and mitochondrial protein-import pathways intrinsically. Results are discussed in the light of the known structural requirements of the two protein trafficking pathways and the formulation of possible treatment strategies for primary hyperoxaluria type 1.


Biochimica et Biophysica Acta | 2003

Alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting in human hereditary kidney stone disease.

Christopher J. Danpure; Michael J. Lumb; Graeme M. Birdsey; Xiaoxuan Zhang

The pyridoxal-phosphate (PLP)-dependent enzyme alanine:glyoxylate aminotransferase (AGT) is mistargeted from peroxisomes to mitochondria in patients with the hereditary kidney stone disease primary hyperoxaluria type 1 (PH1) due to the synergistic interaction between a common Pro(11)Leu polymorphism and a PH1-specific Gly(170)Arg mutation. The kinetic partitioning of newly synthesised AGT between peroxisomes and mitochondria is determined by the combined effects of (1) the generation of cryptic mitochondrial targeting information, and (2) the inhibition of AGT dimerization. The crystal structure of AGT has recently been solved, allowing the effects of the various polymorphisms and mutations to be rationalised in terms of AGTs three-dimensional conformation. Procedures that increase dimer stability and/or increase the rate of dimer formation have potential in the formulation of novel strategies to treat this otherwise intractable life-threatening disease.


Proceedings of the Royal Society of London B: Biological Sciences | 2005

A comparative analysis of the evolutionary relationship between diet and enzyme targeting in bats, marsupials and other mammals

Graeme M. Birdsey; Jackie Lewin; Joanna D. Holbrook; Victor R. Simpson; Andrew A. Cunningham; Christopher J. Danpure

The subcellular distribution of the enzyme alanine : glyoxylate aminotransferase (AGT) in the livers of different mammals appears to be related to their natural diets. Thus, AGT tends to be mitochondrial in carnivores, peroxisomal in herbivores, and both mitochondrial and peroxisomal in omnivores. To what extent this relationship is an incidental consequence of phylogenetic structure or an evolutionarily meaningful adaptive response to changes in dietary selection pressure is unknown. In order to distinguish between these two possibilities, we have determined the subcellular distribution of AGT in the livers of 22 new mammalian species, including members of three orders not studied before. In addition, we have analysed the statistical relationship between AGT distribution and diet in all 77 mammalian species, from 12 different orders, for which the distribution is currently known. Our analysis shows that there is a highly significant correlation between AGT distribution and diet, independent of phylogeny. This finding is compatible with the suggestion that the variable intracellular targeting of AGT is an adaptive response to episodic changes in dietary selection pressure. To our knowledge, this is the first example of such a response being manifested at the molecular and cellular levels across the breadth of Mammalia.


Biochemical Journal | 2003

The liver isoform of carnitine palmitoyltransferase 1 is not targeted to the endoplasmic reticulum

Neil M. Broadway; Richard J. Pease; Graeme M. Birdsey; Majid Shayeghi; Nigel A. Turner; E.David Saggerson

Liver microsomal fractions contain a malonyl-CoA-inhibitable carnitine acyltransferase (CAT) activity. It has been proposed [Fraser, Corstorphine, Price and Zammit (1999) FEBS Lett. 446, 69-74] that this microsomal CAT activity is due to the liver form of carnitine palmitoyltransferase 1 (L-CPT1) being targeted to the endoplasmic reticulum (ER) membrane as well as to mitochondria, possibly by an N-terminal signal sequence [Cohen, Guillerault, Girard and Prip-Buus (2001) J. Biol. Chem. 276, 5403-5411]. COS-1 cells were transiently transfected to express a fusion protein in which enhanced green fluorescent protein was fused to the C-terminus of L-CPT1. Confocal microscopy showed that this fusion protein was localized to mitochondria, and possibly to peroxisomes, but not to the ER. cDNAs corresponding to truncated (amino acids 1-328) or full-length L-CPT1 were transcribed and translated in the presence of canine pancreatic microsomes. However, there was no evidence of authentic insertion of CPT1 into the ER membrane. Rat liver microsomal fractions purified by sucrose-density-gradient centrifugation contained an 88 kDa protein (p88) which was recognized by an anti-L-CPT1 antibody and by 2,4-dinitrophenol-etomoxiryl-CoA, a covalent inhibitor of L-CPT1. Abundance of p88 and malonyl-CoA-inhibitable CAT activity were increased approx. 3-fold by starvation for 24 h. Deoxycholate solubilized p88 and malonyl-CoA-inhibitable CAT activity from microsomes to approximately the same extent. The microsomal fraction contained porin, which, relative to total protein, was as abundant as in crude mitochondrial outer membranes fractions. It is concluded that L-CPT1 is not targeted to the ER membrane and that malonyl-CoA CAT in microsomal fractions is L-CPT1 that is derived from mitochondria, possibly from membrane contact sites.


Molecular Biology and Evolution | 2004

Differential Enzyme Targeting As an Evolutionary Adaptation to Herbivory in Carnivora

Graeme M. Birdsey; Jackie Lewin; Andrew A. Cunningham; Michael William Bruford; Christopher J. Danpure


Molecular Biology and Evolution | 2003

Fungal Hydrogenosomes Contain Mitochondrial Heat-Shock Proteins

Mark van der Giezen; Graeme M. Birdsey; David S. Horner; John M. Lucocq; Patricia Dyal; Marlene Benchimol; Christopher J. Danpure; T. Martin Embley


Journal of Biological Chemistry | 2005

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Pia A. J. Huber; Graeme M. Birdsey; Michael J. Lumb; David T. R. Prowse; Tommy J. Perkins; Daniel R. Knight; Christopher J. Danpure


Molecular Biology and Evolution | 2000

Molecular Adaptation of Alanine : Glyoxylate Aminotransferase Targeting in Primates

Joanna D. Holbrook; Graeme M. Birdsey; Ziheng Yang; Michael William Bruford; Christopher J. Danpure


Acta Physiologica Scandinavica | 2000

Intracellular localization of dimethylarginine dimethylaminohydrolase overexpressed in an endothelial cell line

Graeme M. Birdsey; James Leiper; Patrick Vallance

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Michael J. Lumb

University College London

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James Leiper

Imperial College London

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Majid Shayeghi

University College London

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E D Saggerson

University College London

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