FEATURE ARTICLE
The Molecular Anatomy of an Ancient Adaptive Event
Protein engineering identifies the structural basis of a 3.5 billion-year-old adaptation
Antony Dean
Roles of Isocitrate Dehydrogenase
The phenotypes I am interested in belong to the isocitrate dehydrogenases (ICDHs), a family of enzymes found in an overwhelming majority of species. ICDHs catalyze a reaction central to energy production in the citric acid cycle and to the biosynthesis of glutamate, an amino acid. In fact, glutamate biosynthesis is doubly important because it is a primary means by which nitrogen, in the form of ammonia, becomes trapped in biomolecules. Organisms lacking ICDH must obtain energy through fermentation and glutamate from diet.
The specific chemical reaction catalyzed by ICDHs involves a reduction reaction—the transfer of a hydrogen from isocitrate to another molecule, called a coenzyme. The coenzyme will then cede this purloined hydrogen atom in the course of various other reactions necessary for life. In effect, the coenzyme is molecular money, part of a currency recognized by many enzymes, a currency that links and coordinates the various disparate parts of metabolism in much the same way that money greases the disparate parts of an economy.
ICDHs reduce one of two coenzymes, nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP). Despite structural similarities and identical catalytic chemistries (Figure 4), cells use NADH and NADPH (the additional H refers to the purloined hydrogen atom) in very different ways. NADH is used to synthesize adenosine triphosphate (ATP), another coin in the energy currency of life. NADPH is essential for numerous reactions that contribute to cellular maintenance and growth, including the synthesis of certain amino acids, such as glutamate.
All ICDHs display a marked preference for one of the two coenzymes, a preference that depends on metabolic role and cellular localization. NAD-dependent ICDHs are found in mitochondria, the powerhouses of eukaryotic cells, where ATP is synthesized. NADP-dependent ICDHs are found in the cytoplasm, where, among other things, they help reduce excess food to fat (pity). Even ICDHs from the single-celled bacteria, which lack the complex internal organization of eukaryotic cells—those found in plants and animals—display these marked preferences. Most members of the class of bacteria called eubacteria have an NADP-dependent ICDH, although a few have an NAD-dependent ICDH instead. The specific problem I shall tackle is the evolution of coenzyme usage in eubacterial ICDHs: When it happened, why it happened, where it happened and how it happened.
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