Protein-protein interactions in control of energy metabolism / Use of heavy isotopes to investigate metabolic state in living and archaeological subjects
Co-workers: G. Solaini, University of Bologna, Italy, G. Lippe, University of Udine, Italy, G Wegener, University of Mainz, Germany
The H+-ATP synthase is the enzyme responsible for oxidative ATP synthesis in all living organisms, and is, hence, at the centre of cellular energetics. It is a complex enzyme and we have been interested in its structure and catalytic mechanism over many years. A recent interest is the regulation of this enzyme within cardiac cells.
Contrary to the previously accepted dogma, we have shown that in vivo the mammalian ATP synthase does not simply respond to substrate concentrations but is subject to specific regulation by interacting with regulatory proteins.
We have studied the structure of one such protein, IF 1, and its interaction with the ATP synthase. More recently, however, I investigated the role of this protein within the living cell. Using cultured cells and studies with in vivo hearts, we have shown that it responds, inside the mitochondrion, to signals (particularly Ca 2+ ions) sent from the cytoplasm. However, in pathological situations such as ischaemia and hypertension, this regulatory system functions abnormally.
Investigating protein-protein interactions within the living cell is difficult, and has involved some degree of mathematical modelling. This, more theoretical, approach has led to other, rather disparate, research areas. One has been the control of sporulation in B. subtilis, which is regulated by transcription (s) factors, which are modulated by protein-protein interactions dependent on ATP turnover rates. A second area has been the development of the use of heavy isotopes in stable proteins (such as collagen and keratin) to study the effects of diet on body composition. This technique has been applied in archaeology for some time, but we have been able to correlate changes that can be observed in archaeological specimens with events, such as breastfeeding and pregnancy, in living subjects, and thus allow the interpretation of the archaeological data on a sound empirical base.
- Solaini, G. and Harris, D.A. (2005) Biochemical dysfunction in heart mitochondrial exposed to ischaemia and reperfusion. Biochem. J. 390, 377-94
- Di Pancrazio, F., Mavelli, I, Isola, M, Losano, G, Pagliaro, P, Harris, D.A. and Lippe, G (2004) In vitro and in vivo studies of F OF 1 ATP synthase regulation by the inhibitor protein IF 1 in goat heart. Biochim. Biophys. Acta 1659, 52-62
- Clarkson, J., Shu, J-C, Harris, D.A., Campbell, ID and Yudkin, M.D. (2004) Fluorescence and kinetic analysis of the SpoIAB phosphorylation reaction, a key regulator of sporulation in B. subtilis. Biochemistry 43, 3120-28
- Fuller, B.T., Fuller, J.L., Sage, N.E., Harris, D.A., O’Connell, T.C. and Hedges, R.E.(2005) Nitrogen balance and d 15N: why you’re not what you eat during nutritional stress. Rapid Comm. Mass Spectrom. 19, 2497-2506
- Fuller, B.T., Fuller, J.L., Harris, D.A., and Hedges, R.E. (2006) Detection of breast feeding and weaning in modern human infants with carbon and nitrogen stable isotope ratios. Amer. J. Phys. Anthropol. 129, 279-293
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