orals 5th Asia-Pacific NMR Symposium 2013

A core metabolic enzyme is responsible for phosphine resistance and fundamental metabolic regulation (#82)

Horst Joachim Schirra 1 , Anita Goldinger 1 , Colin Cheng 1 , Paul Ebert 1
  1. University of Queensland, Brisbane, QLD, Australia

The global regulation of metabolism and adaptation to different conditions is a fundamental process of life. It is involved in biological processes as diverse as ageing, the determination of lifespan, and hibernation. In addition, mis-regulation of metabolism is implicated in the development of diseases from obesity to cancer. For this reason, we are investigating the mechanisms of metabolic regulation with a combination of systems biology techniques (most notaby NMR-based metabolomics) and classical biology in a variety of systems ranging from animals to humans.

Our central model system in this respect is the development of resistance in pest insects to the agricultural fumigant phosphine (PH3), which threatens global food security. Recently we have shown that the core metabolic enzyme dilipoamide dehydrogenase (DLDH) is responsible for phosphine resistance in pest insects and C. elegans 1. Phosphine resistance is caused by a mutation in DLDH that also extends lifespan by 30%.

DLDH is a core metabolic enzyme, central to metabolic regulation, and a new class of resistance factor for a redox-active metabolic toxin. As part of multi-enzyme complexes, DLDH participates in four key steps of core metabolism, which are affected differently by phosphine exposure in mutant and wild-type nematodes. Polymorphisms responsible for phosphine resistance cluster around the redox-active catalytic disulfide or the dimerisation interface of DLDH in insects and nematodes providing a mechanistic explanation of phosphine resistance.

This study is an exceptional case in which a combination of systems biology methods has identified a single genetic cause of phenotype change that can subsequently be studied with classical methods. The DLDH containing multi-enzyme complexes are involved in global metabolic regulation, hibernation, and longevity. Further investigation of DLDH via metabolomics, metabolic network modelling, classical biochemistry and structural biology will thus provide insights into these fundamental biological processes.

  1. Schlipalius, DI, Valmas, N, Tuck, AG, Jagadeesan, R, Ma, L, Kaur, R, Goldinger, A, Anderson, C, Kuang, JJ, Zuryn, S, Mau, YS, Cheng, Q, Collins, PJ, Nayak, MK, Schirra, HJ, Hilliard, MA, Ebert, PR (2012): A Core Metabolic Enzyme Mediates Resistance to Phosphine Gas. Science 338, 807-810.