Biological Chemistry - Berezov T. T., Korovkin B. F. 1998

Interrelationship of metabolic processes in the body

Living organisms and their functioning depend continuously on their surrounding environment. The intensity of metabolic exchange with the external environment and The rate of intracellular metabolic processes maintain the constancy of the internal environment and the integrity of the Organism.

As previously noted, METABOLISM in The Human Body does not proceed chaotically; rather, it is integrated and finely tuned. All transformations of organic substances, including anabolic and catabolic processes, are closely interconnected. Specifically, Synthesis and Breakdown processes are interrelated, coordinated, and regulated by neurohormonal mechanisms that direct chemical processes along the required pathways. In the human body, as in living nature generally, there is no independent metabolism of Proteins, Lipids, CARBOHYDRATES, and Nucleic Acids. All transformations are integrated into a holistic metabolic process governed by the dialectical laws of interdependence and interconditionality, which also allows for mutual conversions between individual classes of organic substances. Such interconversions are dictated by the physiological needs of the organism, as well as by the necessity to substitute one Class of organic substances for another when a particular process is blocked due to pathology.

As Krebs and Kornberg pointed out, despite the enormous variety of dietary nutrients (proteins, lipids, carbohydrates), the number of Chemical Reactions ensuring their transformation (breakdown) and energy generation is "remarkably small." These regularities are characteristic of animal and human organisms as well as microorganisms and plants.

Currently, the existence of four major stages in The breakdown of carbohydrate, protein, and lipid molecules—which integrate energy production from primary nutritional sources—has been experimentally established. In Stage I, Polysaccharides are cleaved into Monosaccharides (typically hexoses); lipids break down into glycerol and Higher Fatty acids, while proteins are cleaved into their constituent free Amino Acids. It should be emphasized that these processes are predominantly hydrolytic; therefore, the small amount of energy released is almost entirely utilized by organisms as heat.

In Stage II, monomeric molecules (hexoses, glycerol, fatty acids, and amino acids) undergo further breakdown, during which energy-rich phosphate compounds and acetyl-CoA are formed. Specifically, during Glycolysis, hexoses are cleaved into pyruvic acid and subsequently into acetyl-CoA. This process is accompanied by The formation of a limited number of energy-rich phosphate bonds via substrate-level phosphorylation. Similarly, higher Fatty acids are degraded to acetyl-CoA at this stage, whereas glycerol is oxidized via The Glycolytic Pathway to pyruvic acid and subsequently to acetyl-CoA. For amino acids, the situation in Stage II is somewhat different. When Amino acids are preferentially used as an energy source (during carbohydrate deficiency or Diabetes Mellitus), some are directly converted into metabolites of The Citric Acid Cycle (glutamate, aspartate), others indirectly via glutamate (Proline, Histidine, Arginine), and still others into Pyruvate and subsequently into acetyl-CoA (Alanine, Serine, Glycine, Cysteine). Finally, A number of amino acids, notably leucine and isoleucine, are broken down into acetyl-CoA, while Phenylalanine and Tyrosine yield not only acetyl-CoA but also oxaloacetate via fumaric acid. As can be seen, Stage II can be designated as the stage of acetyl-CoA formation, which essentially serves as a single (common) intermediate product in the Catabolism of major dietary nutrients within Cells.

In Stage III, acetyl-CoA (along with certain other metabolites such as α-ketoglutarate and oxaloacetate) undergoes oxidation ("combustion") in the Krebs di- and Tricarboxylic Acid Cycle. This oxidation is accompanied by the formation of reduced forms of NADH + H⁺ and FADH₂.

In Stage IV, electrons are transferred from the reduced NUCLEOTIDES to oxygen (via the Electron Transport Chain). This process results in the Formation of the end product—Water molecules. Such Electron transport is coupled with ATP synthesis through Oxidative Phosphorylation (see Chapter 9).

It should be noted that, In addition to mutual transitions among different classes of substances within the organism, more complex forms of interconnection have been proven to exist. Specifically, the rate and direction of any chemical reaction are determined by Enzymes—that is, proteins that exert a direct influence on lipid, carbohydrate, and NUCLEIC ACID METABOLISM. In turn, the synthesis of any enzymatic protein requires the participation of DNA and all Three types of Ribonucleic Acids: tRNA, mRNA, and rRNA. Adding to this The Influence of Hormones, as well as the breakdown products of one class of substances (e.g., biogenic amines) on the metabolism of other classes of Organic compounds, one can understand the remarkable harmony and coordination of the vast array of chemical processes occurring within the organism. Many of these processes were discussed in detail in the descriptions of the Metabolism of individual substance classes (see Chapters 10–12). This chapter briefly presents Examples of mutual transitions among individual Structure/83.html">Structural elements of proteins, lipids, carbohydrates (Fig. 15.1), and nucleic acids during their transformations and metabolism.

In addition to direct transitions of metabolites among these classes of substances into one another, a close energetic relationship exists, whereby energy demands can be met by The oxidation of a single class of organic substances when the Dietary intake of others is insufficient. The Importance of proteins (particularly enzymes, hormones, etc.) in the metabolism of all types of chemical compounds is self-evident and requires no proof. The significant role of PROTEINS AND AMINO acids in the synthesis of various specialized compounds (purine and pyrimidine nucleotides, Porphyrins, biogenic amines, etc.) was noted earlier. Ketogenic amino acids, which yield acetoacetic acid (acetoacetyl-CoA) during metabolism, can directly participate in the synthesis of Fatty Acids and sterols. Glycogenic Amino acids can be utilized similarly via acetyl-CoA, but only after prior conversion into pyruvate. Certain Structural components of specialized lipids, particularly phosphoglycerols, derive their origin from Amino Acids and their derivatives, such as serine, ethanolamine, sphingosine, and Choline. It must be emphasized that The conversion of the carbon skeletons of ketogenic or glycogenic amino acids into fatty acids is an irreversible process, although one cannot rule out the possibility of the partial synthesis of glutamate and, indirectly, Other Amino Acids from fatty acid breakdown products—acetyl-CoA—via The Tricarboxylic Acid Cycle, which includes α-ketoglutarate. At the same time, the Synthesis of the carbon skeletons of certain glycogenic amino acids from the glycerol of neutral fats proceeds entirely via pyruvate.

Fig. 15.1. Interrelationship of proteins, fats, and carbohydrates.

The Hydrolysis products of dietary and tissue triacylglycerols, specifically higher fatty acids, directly participate in the formation of complex proteins—Blood Plasma Lipoproteins. As components of lipoproteins, which thus serve as a transport form of fatty acids, they are delivered to target Organs where the fatty acids serve either as an energy source (cardiac and Skeletal Muscle) or as precursors for the synthesis of tissue triacylglycerols, followed by their deposition in cells of various organs (lipid depots).

Evidence has been obtained for the Synthesis of glucose from the majority of amino acids. For Certain amino acids (alanine, aspartic acid, and glutamic acid), the connection to Gluconeogenesis is direct, whereas for others it is mediated through ancillary metabolic pathways. It should be emphasized that three α-keto acids (pyruvate, oxaloacetate, and ketoglutarate), derived respectively from alanine, aspartate, and glutamate, not only serve as Starting Material for glucose synthesis but also act as unique Cofactors in the breakdown of acetyl residues from all classes of dietary nutrients within the Krebs cycle to generate energy.

The synthesis of Essential Amino Acids from carbohydrate and lipid metabolic products does not occur in animal organisms. Animal cells lack the enzyme systems that catalyze the synthesis of the carbon skeletons of these amino acids. At the same time, the organism can develop normally on an exclusively protein diet, which also indicates the feasibility of synthesizing carbohydrates from proteins. The process of carbohydrate synthesis from amino acids is termed gluconeogenesis. It has been proven directly in experiments on animals with experimental diabetes: more than 50% of administered protein is converted into glucose. As is known, In diabetes the organism loses The ability to utilize glucose, and energy demands are met through the oxidation of amino acids and fatty acids. It has also been proven that the initial substrates for gluconeogenesis are those amino acids whose breakdown is accompanied by the direct or indirect formation of pyruvic acid (e.g., alanine, serine, Threonine, and cysteine). Furthermore, evidence exists for a unique cyclic process within the organism—the glucose-alanine cycle—which participates in the fine Regulation of Blood glucose concentration during periods between meals when the organism experiences a glucose deficit. The sources of pyruvate in this process are the aforementioned amino acids, which are formed in Muscles during protein breakdown and transported to the Liver, where they undergo deamination. The resulting ammonia is detoxified in the liver by participating in the synthesis of urea, which is excreted from the organism. The deficit of Muscle Proteins is subsequently replenished by the intake of dietary amino acids.

The energetic value of food exerts a definite influence on Protein metabolism, as monitored by nitrogen balance. Thus, if dietary energy intake falls below the minimum level, an increase in nitrogen excretion is observed, and conversely, an increase in dietary energy intake leads to a decrease in urinary nitrogen excretion.

Complex connections exist between The Citric Acid cycle and the Ornithine Urea Cycle, which determine, to a certain extent, the reaction rates dependent on the energy demands of The Cell and the concentrations of metabolic end products. As was demonstrated (see Chapter 12), fumaric acid is formed during the breakdown of argininosuccinic acid, the synthesis of which in turn requires the presence of The amino acid aspartate. The resulting fumaric acid (derived from the amino acid precursor aspartate) then enters the citric acid cycle and, under the action of two enzymes of this cycle—fumarate hydratase and malate dehydrogenase—is converted into oxaloacetate, which is reconverted into aspartate with the participation of a specific transaminase. This establishes a unique aspartate-argininosuccinate shunt connecting the citric acid cycle with The urea cycle (Fig. 15.2). Thus, via this unusual coupled mechanism, the reactions of both cycles (urea cycle and di- and tricarboxylic acid cycle) become intertwined. This mechanism has been termed the "Krebs bicycle" (The "Krebs bicycle").

Fig. 15.2. The "Krebs Bicycle". (Printed with the kind permission of Dr. David L. Nelson and Dr. M.M. Cox, 1993.)

The presented general scheme (see Fig. 15.1) also shows that various pathways exist for the interconversion of fats and carbohydrates. The practice of livestock fattening has long confirmed the possibility of synthesizing fats from dietary carbohydrates. From an energetic standpoint, the conversion of carbohydrates into fats should be viewed as the storage and deposition of energy, although fat synthesis is accompanied by Energy Expenditure, which is released anew upon the oxidation of fats within the organism. Glycerol, which is part

of triacylglycerols and phosphoglycerols, can be readily formed from glycolytic intermediates, specifically glyceraldehyde-3-phosphate. It should be emphasized, however, that the principal pathway for converting carbohydrates into fats is the formation of higher fatty acids from acetyl-CoA, which is produced through The oxidative decarboxylation of pyruvate. The latter reaction is practically irreversible, and consequently, the FORMATION OF CARBOHYDRATES from higher fatty acids virtually does not occur. Thus, the synthesis of carbohydrates from fats can, in principle, proceed only via glycerol, although under normal conditions the reaction proceeds in the reverse direction—that is, toward the synthesis of fats from glycerol generated during carbohydrate oxidation. Acetyl-CoA, produced during the metabolism of carbohydrates, fats, and a number of amino acids, serves as a starting substrate both for the synthesis of fatty acids (and consequently lipids in general) and for the tricarboxylic acid cycle. The oxidation of acetyl-CoA in this cycle requires oxaloacetate, which is the second key substrate in the Krebs cycle. Oxaloacetate can be synthesized from pyruvic acid and CO₂ via a carboxylation reaction or formed from aspartic acid during Transamination with α-ketoglutarate. Two molecules of acetyl-CoA condense to form acetoacetic acid (acetoacetate), which is the source of other Ketone Bodies in the organism, specifically β-hydroxybutyric acid (β-hydroxybutyrate) and acetone (see Chapter 11). It must be emphasized that acetoacetic and β-hydroxybutyric acids are often regarded as transport forms of active acetic acid, delivering it for oxidation in the Krebs cycle within peripheral Tissues. These same Condensation reactions of two acetyl-CoA molecules constitute the initial steps of Cholesterol synthesis, which in turn serves as a precursor for Steroid Hormones, vitamin D₃, and Bile acids. The latter, in the form of conjugated bile acids, perform an important emulsifying function during the Digestion of dietary lipids in the intestine, as well as a transport function by facilitating the absorption of higher fatty acids.

Mention should also be made of the utilization of galactose and, in part, glucose for The Biosynthesis of cerebrosides and Glycolipids, which perform important and specific Functions in The activity of the Central Nervous system. This synthesis involves not free monosaccharides, but hexosamines (galactosamine and glucosamine), the biosynthesis of which in turn requires the provision of the amide nitrogen of glutamine, thereby integrating the metabolism of carbohydrates, lipids, and proteins.

In recent years, a considerable body of experimental data has accumulated indicating the existence in living organisms of numerous regulatory mechanisms that exercise Metabolic control and ensure both The interconversions of proteins, lipids, and carbohydrates and the integration of energy. Without denying the importance of Other types of Metabolic Regulation (see Chapters 8, 9), it should be emphasized that the driving force behind substance interconversions and metabolic rate is most likely the energetic state of the cell, specifically the ATP level (more precisely, the AMP/ATP ratio). Thus, at low AMP concentrations and high ATP concentrations (a state conventionally referred to as "energization"), cells exhibit a sharp decrease in the glycolytic breakdown of glucose, caused by the action of these nucleotides on the key glycolytic enzyme Phosphofructokinase and on fructose-6-phosphatase. As a result, not only fructose-6-phosphate accumulates in the cells, but also its precursor, glucose-6-phosphate. Acting as a positive modulator of the enzyme Glycogen synthase, the latter stimulates the synthesis of the polysaccharide glycogen. At low ATP concentrations (and correspondingly high AMP levels), cells show a stimulation of Glycolysis and Pyruvate Oxidation in the citric acid cycle, which helps supply the cells with energy. However, at low AMP concentrations, a decrease in the rate of the tricarboxylic acid cycle occurs due to the inhibition of isocitrate dehydrogenase activity, which correspondingly leads to a reduced rate of ATP synthesis and the accumulation of isocitric acid. As is known, the latter increases the activity of another enzyme, acetyl-CoA carboxylase, which in turn catalyzes The First stage of the conversion of acetyl-CoA into fatty acids. Through these circumstances, the cell diverts the acetyl-CoA molecule produced during glycolysis away from the energetic pathway and toward lipid synthesis and storage in depots. At the same time, when the rate of ATP utilization is restored—which is typically observed during fatty acid synthesis—a corresponding increase in the AMP level helps lower the citric acid concentration and consequently inhibits lipid synthesis.

The examples listed by no means exhaust the full diversity of organic substance interconversions that constantly take place in living organisms. Only the main, primary channels and pathways for the transformation of general classes of substances are presented here, along with the key substrates and enzyme systems that ensure the constancy of chemical components and tissues alongside the dynamic nature of living structures.

Thus, the rate of breakdown of certain nutrients and the biosynthesis of others are determined primarily by the physiological state and the organism's demands for energy and metabolites. Thanks to the dynamism and coordination of metabolic activity, the MACROSCOPIC AND MICROSCOPIC constancy of all forms of life is ensured. Elucidating the fundamental problems of the Structure and function of individual Biomolecules can serve as a basis for uncovering both the MOLECULAR MECHANISMS OF chemical processes underlying the composition and functions of individual cells and the whole organism, and the processes ensuring the biological individuality of living organisms. Any disturbances in this dynamic status of the organism are accompanied by The Development of pathology, the severity and duration of which will be determined by the degree of damage to the structure and function of individual Molecular and supramolecular components of cells.