Biochemistry and Molecular Biology - Belyasova, N. A. 2002

Metabolism. Processes Requiring Energy Input
Metabolic Integration
Metabolic Regulation

Chemical Reactions occurring within Cells are catalyzed by Enzymes. It is hardly surprising, therefore, that most ways of regulating METABOLISM are based on two leading processes: changes in Enzyme Concentration and enzyme activity. These Metabolic regulation pathways are characteristic of all cells and are carried out through various mechanisms in response to diverse signals. In addition, cells possess supplementary means of regulating metabolism, The Diversity of which is best examined across several Levels of Organization.

Regulation at the Transcription level. This type of regulation is discussed in Chapter 3 using several Examples of positive and negative Control of transcription in prokaryotic genes. This mechanism primarily regulates The amount of mRNA that determines the Structure of enzymes, as well as histone and ribosomal and transport Proteins. While lacking catalytic activity, the latter group plays a major role in altering the rates of corresponding processes (such as chromosome and ribosome formation, and the Transport of substances across membranes), and consequently, overall metabolism.

Gene transcription is regulated by regulatory proteins whose structure is determined by specific genes (regulators), their complexes with ligands (e.g., lactose during transcription induction or Tryptophan during repression), cAMP-CAP complexes, guanosine tetraphosphate, and, in some cases, proteins that are products of The Cell's own Gene Expression. Such key signaling molecules as cAMP and guanosine tetraphosphate are of particular importance in these processes. It can be said that cAMP signals an energy deficit—specifically, the absence of glucose—to the cell. In response, the transcription frequency of structural genes responsible for the Catabolism of alternative carbon and Energy Sources increases (activation of catabolic operons, catabolite repression, Chapter 3). Guanosine tetraphosphate (guanosine 5'-diphosphate 3'-diphosphate) serves as a signal for amino acid starvation. This nucleotide binds to RNA polymerase and alters its affinity for the promoters of various genes. As a result, the expression of genes responsible for The Biosynthesis of CARBOHYDRATES, Lipids, NUCLEOTIDES, and Other Compounds decreases, whereas the expression of other genes, particularly those determining protein proteolysis, increases.

Transcription is most frequently regulated by changing the frequency of Transcription initiation events; however, The rate of transcription elongation and the frequency of its premature termination can also be regulated. Elongation and termination events are primarily influenced by the conformational state of the DNA or the mRNA itself (such as the presence of stop signals or hairpin structures).

Allosteric Introduction/15.html">Regulation of enzyme Activity. This type of regulation is among the fastest and most flexible; it is mediated by effector molecules that interact with the allosteric site of an enzyme (Chapter 6). Like Operon regulation, Allosteric Regulation targets Key Enzymes in specific metabolic pathways. Thus, the rate of an entire biosynthetic or catabolic process depends on one—or less frequently, several—Reactions Catalyzed by these key enzymes.

Regulation is of particular importance for the biosynthesis of Proteinogenic Amino Acids. Because There are 20 such amino acids, and each is represented in the total cellular protein of different organisms in a specific proportion, a very precise regulation is required to coordinate the synthesis of individual amino acids. Such control prevents overproduction, and the release of amino acids from the cell occurs only in microorganisms with impaired regulation.

An example of The regulation of aspartate-family Amino acid biosynthesis in enterobacteria is shown in Fig. 19.3. Four amino acids share a common precursor: aspartic acid. Its conversion to aspartyl phosphate in E. coli is catalyzed by three isoenzyme forms of aspartokinase, each subject to repression and/or inhibition by different End products of this branched metabolic pathway. Homoserine dehydrogenase synthesis is regulated in a similar manner.

Of note is the existence of a feedback mechanism, whereby the end products of metabolic processes regulate the synthesis rate and/or activity of the enzymes catalyzing the initial steps of these metabolite pathways.

Allosteric effectors can be A wide variety of substances: substrates and end products of metabolic pathways, and occasionally intermediate metabolites; nucleoside diphosphates and nucleoside triphosphates, as well as reducing equivalent carriers in catabolic processes; cAMP and cGMP in cascade reactions, which regulate The activity of enzymes (such as protein Kinases) involved in the Covalent Modification of proteins; Metal Ions; and numerous other compounds. Examples of allosteric enzyme regulation are provided in Chapter 6 and other sections.

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Fig. 19.3. Diagram of the Regulation of Synthesis and activity of enzymes involved in the aspartate-family amino acid biosynthetic pathway in E. coli. The genes encoding aspartokinase 1, homoserine kinase, and Threonine synthetase form the threonine operon, which is multivalently repressed by threonine and isoleucine.

Covalent modification of enzymes. This type of ENZYME ACTIVITY REGULATION is also referred to as interconversion of enzymes, as the core process involves converting active enzyme forms into inactive ones and vice versa. The features and examples of covalent modification are described in Chapter 6. These processes are subject to diverse controls, including hormonal control. A classical example of enzyme interconversion is the Regulation of Glycogen metabolism in the Liver.

The synthesis rate of this reserve polysaccharide is controlled by glycogen synthase, while its breakdown is catalyzed by Glycogen phosphorylase. Both enzymes can exist in active and inactive forms. During starvation or stressful situations, the Hormones adrenaline and Glucagon are released into the Blood; they bind to receptors on the Plasma Membranes of cells and activate the enzyme adenylate cyclase (which catalyzes cAMP synthesis) via G-proteins. cAMP binds to protein kinase A and activates it, leading to the phosphorylation of Glycogen synthase and its conversion into an inactive form. Glycogen synthesis then ceases. In addition, through a cascade of reactions, protein kinase A triggers the phosphorylation of glycogen phosphorylase, activating it to begin glycogen breakdown. Another hormone, Insulin, also influences Glycogen Synthesis and degradation processes. In this example, hormones serve as signaling molecules, while G-proteins and cAMP act as intermediaries. Enzyme interconversions are carried out via phosphorylation-dephosphorylation cycles.

Hormonal regulation. This type of metabolic regulation involves hormones—signaling substances produced by endocrine gland cells; consequently, hormonal regulation is unique to higher organisms. The Action of Hormones on Glycogen Metabolism, where enzyme activity is regulated via covalent modification, was described above. In addition, hormones can influence transcription rates (operon regulation).

From the specialized cells where they are synthesized, hormones enter the bloodstream and are transported to target cells that possess receptors capable of binding the hormones and thereby perceiving the hormonal signal. The binding of a hormone to its receptor triggers a cascade of reactions involving intermediary molecules, culminating in a cellular response. Lipophilic hormones bind to intracellular receptors (proteins) and regulate the transcription of specific genes. Hydrophilic hormones act on target cells by binding to receptors on The Plasma Membrane.

Besides hormones, other signaling substances act in a similar manner: mediators, Neurotransmitters, and growth factors. There is no sharp boundary distinguishing hormones from these substances. Mediators are signaling substances produced not by Endocrine glands, but by various cell types. Examples include histamine and Prostaglandins, which exhibit hormone-like activity.

Neurotransmitters are considered to be signaling substances produced by Cells of the Central Nervous system.

Changes in metabolite concentration. An important condition ensuring a high rate of a given metabolic pathway is the concentration of substrates. This can depend on the intensity of other processes that also consume these substrates (competition), or on the transport rate of these substances across membranes (plasma or organelle membranes). In particular, Eukaryotic cells can regulate metabolism by compartmentalizing and redistributing metabolites.

Furthermore, the rate of metabolic processes is determined by the concentration of Cofactors. For example, Glycolysis and the TCA cycle are regulated by ADP availability (Chapters 10 and 11) through Changes in the activity of key allosteric enzymes.

Post-transcriptional and post-translational modification of macromolecules. These processes are also described in the relevant sections (Chapter 3). The modification and/or Processing of primary RNA transcripts occur at varying rates, which determines the concentration of mature RNA molecules capable of Translation, and thus the intensity of Protein Synthesis. In turn, Peptides must also be modified before becoming mature proteins; in the case of enzymes, this involves covalent modification.