About the Cover
Cover
Key elements of the Krebs cycle, which is at the core of intermediary metabolism, have been known since 1937 when they were proposed by Hans Krebs, who was awarded a Nobel Prize in 1953 for his discoveries. Starting in the 1980s, a new version of the Krebs cycle began to emerge. In the original version, acetate was oxidized to carbon dioxide, converting the energy to reduced intermediate products and ultimately to ATP. In the new version, the process runs in the opposite direction. This reverse pathway is called the reductive tricarboxylic acid (rTCA) cycle. It is an engine of synthesis rather than of energy production. Reduced compounds are the input, running the cycle essentially backward, incorporating carbon dioxide in an autocatalytic pathway that synthesizes the components necessary for the cell’s organic compounds.
The organisms carrying out this pathway are largely thermophilic, autotrophic anaerobes. Their chemistry was being understood at the same time that deep oceanic vents were being discovered and suggested as a locus of biogenesis. This led to experiments in high-temperature, high-pressure organic chemistry. These studies supported the plausibility of the rTCA or closely related pathways as components of the biochemistry of earth’s earliest inhabitants. This view of metabolism was consistent with the very low oxygen concentration on earth for the first 2 billion years of life. A paradigm emerged that reductive autotrophy preceded heterotrophy and chemoautotrophy preceded photoautotrophy.
Since the early 1990s, these views have invigorated studies on the origin of life. The cycle shown on the cover is the core of the rTCA cycle and may well be at the core of archean biochemistry. The recent sequencing of bacterial genomes has permitted the discovery of genes that are characteristic of the rTCA cycle. Sequencing has also provided data-bases for searching out those genes in contemporary bacteria. The subsequent discovery of horizontal gene transfer has contributed interest in finding genes in unexpected organisms.
As Vijayasarathy Srinivasan and Harold J. Morowitz detail in their article on page 1, a surprising outcome of such data mining is the discovery of ancient genes for reductive metabolism in the genomes of contemporary pathogens that normally demonstrate aerobic metabolism. These genes permit the pathogens to persist for long periods in oxygen-poor niches in their hosts. Two such genes code for 2-oxoglutarate synthase and citrate lyase. This behavior is a profound example of the relatedness of all life and demonstrates the role that horizontal gene transfer may play in the development of disease. Because the ancient genes are not present in the host, they are potential targets for therapeutic agents. The search for unexpected genes in pathogenic microorganisms may provide a general path for the design of new drugs.
Credits: V. Srinivasan and H. J. Morowitz (George Mason University) for the metabolic pathway diagram; James Kermode for the helix-sequence background; and Beth Liles (Marine Biological Laboratory) for cover layout.
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Copyright © 2006 by the Marine Biological Laboratory.
