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Principles of Metabolic Control 1 PRINCIPLES OF METABOLIC CONTROL WILLIAM C. PLAXTON KEY CONCEPTS eclipsed areas of traditional biochemistry such as protein chemistry, enzymology, and metabolic control. With The ability to control the rates of metabolic processes in many genomes sequenced and others nearing completion, response to changes in the internal or external environment the next step is the less straightforward task of analyzing is an indispensable attribute of living cells that must have the expression and function of gene products (proteins), arisen with life’s origin. This adaptability is necessary for as well as more thoroughly elucidating metabolism and conserving the stability of the intracellular environment its control. The task of completing the picture of all cellu- (homeostasis), which is, in turn, essential for maintaining lar proteins, their actions and reactions, is one of the an efficient functional state. In the absence of such biggest challenges facing life science researchers today. control, all metabolic processes would achieve a state of Although molecular biology has generated many impress- equilibrium with the external environment. For example, ive techniques [e.g., protein overexpression, site-directed the intracellular storage of a fuel macromolecule such as mutagenesis, metabolic engineering, complementary deox- glycogen would be impossible since there is an enzyme yribonucleic acid (cDNA) microarrays, etc.] for assessing (glycogen phosphorylase) dedicated to catalyzing the various aspects of protein/enzyme structure–function and breakdown of this storage polyglucan into its constituent regulatory control, one cannot deduce the properties of a glucosyl units. Obviously, the existence of glycogen as an functional protein or the kinetic and regulatory properties important energy store in animal tissues implies that the of an enzyme solely from genetic information. Moreover, activity of glycogen phosphorylase is carefully controlled recent animal, plant, and microbial genome sequencing so as to allow this fuel to be utilized as dictated by the projects have revealed a plethora of gene sequences that needs of the organism. Indeed, elaborate regulatory mech- encode proteins having unknown functions. Furthermore, anisms have been discovered that affect glycogen phos- many organisms whose genomes have been sequenced phorylase activity, thereby allowing wide variations in the have not had their metabolism extensively studied. Where rate of glycogen breakdown in vivo. The aim of this feasible, their metabolic phenotype is determined using chapter is to outline the biochemical regulatory mechan- annotated genome sequence data. Thus, there appears to isms that are believed to be the most important in metabolic be a resurgence of interest in protein, enzymological, and control. Practical aspects for the study of metabolism and metabolic research for understanding biological processes its control, as well as the advantages and disadvantages in the postgenome era. Efficient approaches are needed of qualitative versus quantitative approaches to metabolic for determining: (a) the function of unknown gene pro- control, will also be highlighted. ducts, (b) protein expression in different cells under various conditions, (c) covalent modifications of proteins in response to different stimuli, (d) protein–protein inter- Metabolic Renaissance in Postgenome Era? actions, (d) the relationship between protein structure and The remarkable advances in molecular genetics that have protein function, and (e) the sophisticated mechanisms occurred over the past couple of decades have somewhat that serve to control the flux of metabolites through specific Functional Metabolism: Regulation and Adaptation, edited by Kenneth B. Storey. ISBN 0-471-41090-X Copyright # 2004 John Wiley & Sons, Inc. 1 2 PRINCIPLES OF METABOLIC CONTROL metabolic pathways in vivo. Novel methods are also being of blood glucose is regulated (kept constant) mainly by developed to map proteomes (i.e., the proteins encoded by controlling (varying) fluxes of metabolic pathways (i.e., the genome) and to discover new enzymes of interest. glycogen breakdown versus synthesis, glycolysis, gluco- neogenesis) in hepatocytes. Regulation and control are properties of highly elaborate metabolic systems. An Metabolic Engineering ongoing challenge is to link our knowledge of molecular, Since it is now possible to manipulate nucleic acids and reductionist-based, enzyme control mechanisms to organ- gene expression at will, an important goal of biotechnology ism-level explan-ations of metabolic regulation. is to modify (usually enhance) the output of specific bio- synthetic pathways via the process of metabolic engineer- Complexity of Metabolism and Concept of ing. Contemporary genetic engineering techniques have Biochemical Unity created the potential to directly modify the metabolism of a target organism in a desired fashion. However, the As protein catalysts, enzymes vastly accelerate the rates of ability to manipulate an organism’s genetics has thus far chemical reactions without themselves undergoing a per- transcended our ability to predict the effects of these manent change. As each cellular reaction is catalyzed by manipulations on metabolism. Our lack of a thorough its own enzyme, every cell contains a large number of appreciation for, and understanding of, metabolic control different enzymes. Although a “simple” prokaryote, such is reflected by the meager results from most attempts to as Escherichia coli, is only about 1/500th the size of a apply the powerful tools of molecular biology and genetic typical eukaryotic cell, each E. coli cell contains about transformation to the practical goal of metabolic engineer- 3000 different proteins, at least 90% of which are ing. Many unsuccessful efforts at so-called shotgun meta- enzymes. The metabolic complexity of all cells is reflec- bolic engineering have been based upon the misguided ted by the many separate enzymatic reactions that make assumption that if the expression of a gene encoding a par- up the metabolic pathways that collectively constitute ticular enzyme is suitably manipulated, then there will be a metabolism. corresponding change in both the in vivo activity of the Despite its complexity, a general understanding of encoded enzyme as well as the flux (or rate of movement) metabolism has been achieved because common solutions of metabolites through the pathway in which the enzyme to the problem of biochemical design have been evolved. functions. “Rational” metabolic engineering is a longer- Thus, the types of substrates, cosubstrates, cofactors, term, but arguably more scientific and interesting process fuels, and types of metabolic pathways used are common that involves the targeted and purposeful alteration of a to most cells. This is the concept of biochemical unity.In specific metabolic pathway. It does not necessarily general, biochemical unity also applies to metabolic regu- depend upon altering the concentration of an enzyme but lation and metabolic control. Comparative biochemistry could be carried out by introducing a mutant (or hetero- has revealed that the types of control mechanisms found logous) enzyme with altered control properties. Apart in metabolic pathways are similar from one organism to from an ability to manipulate nucleic acids, rational meta- the next. However, it is the implementation of these bolic engineering also requires a strong background in designs—the regulatory details—that cannot only differ protein/enzyme and metabolic biochemistry. widely from species to species but can differ widely for similar metabolic pathways in different cell types of a single organism, or even within different organelles of a Metabolic Regulation versus Metabolic Control single cell. Although biochemists frequently employ the terms regu- For example, citrate synthase, which catalyzes the lation and control interchangeably, the need to discriminate reaction acetyl-CoA þ oxaloacetate ! citrate þ CoA, is between these terms has been emphasized (Fell, 1997). controlled in dissimilar manners in different cells. In respir- Metabolic control refers to adjusting the output of a meta- ing animal cells, a major function for this enzyme is in the bolic pathway in response to an external signal. By con- citric acid cycle that operates in the mitochondria in con- trast, metabolic regulation occurs when an organism junction with oxidative phosphorylation to produce adeno- maintains some variable relatively constant over time, sine 50-triphosphate (ATP). Here, the overall end product, despite fluctuations in external conditions. Homeostasis is ATP, feeds back to inhibit citrate synthase. This regulatory therefore a consequence of metabolic regulation, which mechanism is logical since at high ATP levels, the ATP- itself may be a result of metabolic control. For example, generating citric acid cycle will then be inhibited, but if the regulation of mammalian blood glucose is largely due ATP levels fall, substrate catabolism by the cycle will to the secreted peptide hormones glucagon (“starved” speed up. In E. coli, however, citrate synthase and the signal) and insulin (“fed” signal) controlling intracellular citric acid cycle have a different function. This bacterium metabolism within the liver. In this case, the concentration lives a mainly anaerobic life, generating its ATP primarily BASIS OF METABOLIC CONTROL 3 via the fermentation of glucose by glycolysis. The main role any reactions that could lead to artifactual alterations in of the citric acid
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