Another small cog in the 'hub' of metabolism unraveled

November 28, 1999

Related structure solved of the only membrane-embedded enzyme of the citric acid cycle / Key function in metabolism New insights into the mechanism of the hub of metabolism, the citric acid cycle, have been obtained by scientists at the Max Planck Institute of Biophysics and the Institute of Microbiology of the J. W. Goethe University, both located in Frankfurt am Main, Germany. Using X-ray crystallography, they have determined the three-dimensional structure of an enzyme related to succinate dehydrogenase, a key enzyme in the citric acid cycle (nature, 25 November, 1999).

Life is work and requires energy, that is also true at a cellular level. In order to fulfill their various tasks, cells make use of the energy stored in organic molecules. With the help of their enzymes, they systematically break down complex organic molecules and form more simple, less energy-rich, products.

The most efficient and most frequently used way involves cellular respiration. This commences with glucose or other organic compounds. Consuming oxygen, it eventually generates water, carbon dioxide, and in particular also energy-rich ATP and heat. The cellular generation of energy encompasses three metabolic pathways: glycolysis, the citric acid cycle, and the respiratory chain. The first two pathways, glycolysis and the citric acid cycle, break down glucose and other organic compounds in a step-wise manner. In the respiratory chain, the energy is released and can be used by the mitochondria for the generation of the energy "currency" ATP.

The citric acid cycle or Krebs' cycle is the hub of metabolism. It is responsible for the catabolism of carbohydrates, fatty acids and amino acids, and it is also an important source of intermediates for the production of other biochemical compounds. One of the key enzymes in this process is succinate dehydrogenase. It is embedded in the mitochondrial membrane and couples the citric acid cycle to the respiratory chain. The coupled action of these two pathways is a major source of metabolic energy (see Fig. 1).In order to obtain detailed insight into the function of a biological macromolecule such as succinate dehydrogenase, one has to know its three-dimensional structure. However, the structural analysis of an enzyme consisting of several thousand atoms can be a difficult and time-consuming task. Initially, one has to find conditions for obtaining suitable crystals of the respective protein. Then the technique of X-ray crystallography can be applied. The regular array of protein atoms in the crystal diffracts X-rays, leading to a pattern of spots with different intensities on a detector film. On the basis of these diffraction patterns, computer programs can then create maps of electron density for the enzyme. Comparison of the information from the electron density to the previously determined primary structure of the enzyme enables the scientists to build a three-dimensional atomic model of the enzyme. This model can then be displayed and analysed on a graphics computer.

To date, no successful crystallization of the succinate dehydrogenase enzyme has been reported. There is, however, an enzyme of very similar composition, called fumarate reductase. It plays an important role in the metabolism of anaerobic bacteria. Scientists at the Max Planck Institute of Biophysics and at the Institute of Microbiology, J. W. Goethe University in Frankfurt, Germany, have obtained suitable crystals of this enzyme from the anaerobic bacterium Wolinella succinogenes. This has allowed them to solve the three-dimensional structure of this enzyme at high resolution (2.2 angstroems). It consists of a dimer, with each monomer containing the three different subunits A, B, and C (see Fig. 2). The large hydrophilic subunit A contains the site of fumarate reduction and the covalently bound prosthetic group flavin adenine dinucleotide (FAD). The smaller hydrophilic subunit B contains three iron-sulphur centres. The hydroquinone-oxidizing membrane-embedded subunit C binds two haem b groups. On the basis of the structure, a pathway of electron transfer can be traced from the two haem groups of subunit C via the three iron-sulphur centres and the FAD to the site of fumarate reduction.

The high resolution of the structure of the enzyme with the bound substrate fumarate allowed the scientists to propose a catalytic mechanism for the reduction of fumarate to succinate. As all of the identified residues are conserved throughout the family of fumarate reductases and succinate dehydrogenases from different species, this mechanism is of general relevance to the whole family of these enzymes.

These findings of the Frankfurt scientists may not only be relevant for basic biochemical research, but also for medical research. For instance, mutations of succinate dehydrogenases have been associated in higher organisms with oxidative stress and ageing and in humans with Leigh's syndrome, a degenerative disease of the nervous system.


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