Dr Kerry Martin Loomes
Research | Current
My interests are in early stage drug discovery and identifying biological targets for disease. My research has spanned diverse biological areas such as alcoholism, cystic fibrosis, amyloid disease, insulin resistance, fatty liver disease, diabetic complications, and kidney stone disease. I am motivated by interesting biology and by discovering new things that will hopefully benefit society. I also have a background in the biopharmaceutical Industry where I was involved in developing preclinical drug candidates. In more recent years I have become interested in natural products and their bioactive components. My research is highly collaborative and inter-disciplinary with active links to industry. I have described some selected examples below to give you an idea of these scientific pursuits.
1. Bunker RD, Bulloch EM, Dickson JM, Loomes KM, Baker EN. Structure and function of human xylulokinase, an enzyme with important roles in carbohydrate metabolism (2013). J Biol Chem. 2013 Jan 18;288(3):1643-52.
Increased fat content in the liver is associated with obesity and thought to contribute to the development of insulin resistance. Strategies to decrease liver fat under these circumstances may therefore be therapeutically beneficial. We identified a metabolic pathway in the liver that contributes to fat production and focussed on the terminal enzyme, xylulose kinase, which acts as a key regulator. In this paper it was conclusively shown that an orphan enzyme corresponded to xylulose kinase. Its crystal structure was solved together with an inhibitor at the active site (right Figure) thereby providing a platform for structure-based design of drugs to reduce fat accumulation in fatty liver.
2. Whiting, L., Danaher, R. N., Ruggiero, K., Chaussade, C., Phillips, A., & Loomes, K. M. (2013). D-chiro -Inositol Attenuates Epinephrine-stimulated Hepatic Glucose Output in the Isolated Perfused Liver Independently of Insulin. Hormone and Metabolic Research. 45: 394-397.
D-chiro -inositol (DCI) is the naturally-occurring cyclic sugar alcohol found in certain foods such as legumes. It has been found to lower blood glucose levels in diabetes and improve insulin sensitivity in people with polycystic ovary syndrome. It is unclear how DCI exerts these effects in the body. We reasoned that it might act by reducing glucose output in the liver as this would explain both the glucose-lowering and insulin-sensitizing effects. This paper showed that DCI did indeed lower glucose production by the liver and was therefore mimicking the effects of insulin This finding opens new opportunities to identify the metabolic processes involved and target them to reduce glucose output by the liver in metabolic disease. The Figure shows the time-dependent reduction in glucose production by the liver by DCI.
3. Fearnley, F., Greenwood, DR., Schmitz, M., Stephens, JM., Schlothauer, R., & Loomes, KM (2012). Compositional analysis of manuka honeys by high resolution mass spectrometry: identification of a manuka-enriched archetypal molecule. Food Chemistry. 132(2) 948-953.
Manuka honey (Medihoney) is approved by the FDA as a wound healing dressing therapeutic. Consequently, there is much interest in the various bioactive substances that mediate these therapeutic effects. We used mass spectrometry technology to unravel the molecular complexity of honey and hopefully identify bioactive manuka-specific compounds. This paper shed new light on the complexity of honey and how the compounds change with both age and floral origin. It also described the identification of a novel manuka-honey specific compound that we were able to show was derived from the nectar of the leptospermum flower. This compound might have utility as a means to fingerprint Manuka honey to prove its authenticity as well as possessing bioactive properties.
4. WALKER, C.S; LI, X.L; WHITING, L; GLYN-JONES, S; ZHANG, S.P; HICKEY, A.J; SEWELL, M.A; RUGGIERO, K; PHILLIPS, A.R.J; KRAEGEN, E.W; HAY, D.L; COOPER, G.J.S; LOOMES, K.M. 'Mice Lacking the Neuropeptide alpha-Calcitonin Gene-Related Peptide Are Protected Against Diet-Induced Obesity', Endocrinology, 151, (9), p4257-4269, 10.1210/en.2010-0284.
For an average person between 50-80% of our energy expenditure is used to maintain our body temperature. This paper showed that mice lacking a peptide hormone, calcitonin gene-related peptide, displayed increased body temperatures (shown by the figure where the right hand animal has increased temperature as indicated by the red colour). These knockout mice were also resistant to the weight promoting effects of high fat diets. These findings provided new insights into the significance of body temperature on body weight and suggested that targeting heat produced by the body might represent a therapeutic approach for weight loss.
5. Aitken, J. F., Loomes, K. M., Scott, D.w, Reddy, S., A. Phillips, R. J., Prijic, G., Fernando, C., Zhang, S., Broadhurst, R., Huillier, P., and Cooper, G. J. S. (2009). Tetracycline treatment retards the onset and slows the progression of diabetes in human amylin transgenic mice (2010). Diabetes Jan;59 (1):161-171.
Amyloid diseases such as Alzheimer’s and Huntington’s are characterized by the existence of amyloid plaques. Diabetes is also characterized by amyloid that surrounds the insulin-producing cells in the pancreas (shown as bright patches in right Figure). This study showed the potential to target the amyloid that occurs in diabetes using a small molecule such as tetracycline. This study showed that tetracycline retarded the onset and progression of the disease and opened the potential to develop therapeutic compounds using tetracycline as a drug lead.
6. CHIEN, V; AITKEN, J.F; ZHANG, S; BUCHANAN, C.M; HICKEY, A; BRITTAIN, T; COOPER, G.J.S; LOOMES, K.M. 'The chaperone proteins HSP70, HSP/DNaJ and GRP78/BiP suppress misfolding and formation of beta-sheet-containing aggregates by human amylin: a potential role for defective chaperone biology in Type 2 diabetes', Biochem. J., 432, p113-121, 2010.
Chaperones assist in the folding of proteins. We hypothesised that these interactions may be important in amyloid diseases where certain proteins form fibril structures that are toxic to cells. This work showed that chaperone interactions may be an important mechanism by which the cellular machinery normally protects itself against amyloid formation within the islet β-cell. They also highlight similar findings involving chaperones with other amyloid diseases and the association between type-2 diabetes and an increased risk of Alzhiemer’s disease. Overall, these findings indicate that defective chaperone biology could play a common underlying role in amyloid diseases. For further information see Loomes (2011) Survival of an islet β-cell in type-2 diabetes: curbing the effects of amyloid cytotoxicity Islets. 3(1):38-9
7. PAYNE, L.S; BROWN, P.M; MIDDLEDITCH, M.J; BAKER, E.N; COOPER, G.J.S; LOOMES, K.M. 'Mapping of the ATP binding domain of human fructosamine-3-kinase related protein by affinity labelling with 5-[p-(fluorosulphonyl)benzoyl]adenosine.', Biochem. J., 416, p281-288, 2008.
One of the consequences of high blood sugar in diabetes mellitus is the modification of proteins by glucose. This process can lead to the formation of compounds known as advanced glycation end-products (AGES) that are damaging to the body. This study investigated an enzyme that removed these “glycated” species and could therefore play a role in diabetic complications. This research provided experimental evidence for a conserved active site topology between this class of enzyme and other kinase enzymes. This information provides a basis for compounds to target this enzyme.
8. Brown, P. M., Caradoc-Davies, T. T., Dickson, J. M., Cooper, G.J.S., Loomes, K.M., & Baker, E.N. (2006) Crystal structure of a substrate complex of mouse kidney myo-inositol oxygenase, a novel di-iron oxygenase with a key role in inositol metabolism. Proc. Natl. Acad. Sci. USA 103(41), 15032-15037
myo-Inositol oxygenase is an enzyme implicated into the development of diabetic kidney disease. The studies described in this paper described the crystal structure of the enzyme, myo-inositol oxygenase. The structure revealed that the breakdown of its substrate, myo-inositol, involved a rich coordination chemistry by virtue of two iron atoms located in close proximity at the active site. An inositol substrate was also “trapped” at the active site (shown in yellow) enabling new mechanistic insights into how this di-iron centre catalysed its breakdown. This paper provided a platform toward the rational design of inhibitors to probe its role in diabetic complications.
Areas of expertise
Proteomics and Biomedicine
Selected publications and creative works (Research Outputs)
- Walker, C. S., Li, X. L., Whiting, L., Glyn-Jones, S., Zhang, S. P., Hickey, A. J., ... Kraegen, E. W. (2010). Mice Lacking the Neuropeptide alpha-Calcitonin Gene-Related Peptide Are Protected Against Diet-Induced Obesity. Endocrinology, 151 (9), 4257-4269. 10.1210/en.2010-0284
Other University of Auckland co-authors: Kathy Ruggiero, Christopher Walker, Debbie Hay, Shaoping Zhang, Anthony Phillips, Mary Sewell, Tony Hickey
- Aitken, J. F., Loomes, K. M., Scott, D. W., Reddy, S., Phillips, A. R., Prijic, G., ... L'Huillier P (2010). Tetracycline treatment retards the onset and slows the progression of diabetes in human amylim/Islet amyloid polyeptide transgenic mice. Diabetes, 59 (1), 161-171. 10.2337/db09-0548
Other University of Auckland co-authors: Anthony Phillips, Jackie Aitken
- Payne, L. S., Brown, P. M., Middleditch, M., Baker, E., Cooper, G. J. S., & Loomes, K. M. (2008). Mapping of the ATP-binding domain of human fructosamine 3-kinase-related protein by affinity labelling with 5'-[p-(fluorosulfonyl)benzoyl]adenosine. Biochem J, 416 (2), 281-288. 10.1042/BJ20080389
Other University of Auckland co-authors: Leo Payne, Martin Middleditch, Edward Baker
- Brownt, P. M., Caradoc-Davies, T. T., Dickson, J. M. J., Cooper, G. J. S., Loomes, K. M., & Baker, E. N. (2006). Crystal structure of a substrate complex of myo-inositol oxygenase, a di-iron oxygenase with a key role in inositol metabolism. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 103 (41), 15032-15037. 10.1073/pnas.0605143103
Other University of Auckland co-authors: James Dickson, Edward Baker