Metabolism in Surgical Patients


Metabolic Science

Metabolism encompasses all of the biochemical and biophysical reactions that maintain the organism-level energy homeostasis necessary for continued cellular life in response to ever-shifting environmental conditions. , Fully understanding the metabolic processes at work in living systems requires exploring the overlap between chemistry, physics, and biology. Conceptually, these processes are organized into pathways in which enzymes and substrates interact in a stepwise manner to achieve certain outputs that are critical to life. These pathways are interlinked and influenced, such that the output of one pathway can serve as either the input or a regulator of another pathway. Metabolic pathways therefore have the capacity to influence and be influenced by one another. These are characterized as either anabolic, serving to build and develop the organism, or catabolic, breaking down components of the organism. , Processes from both of these categories work in concert under tight regulation to achieve the major goals of metabolism: the maintenance of life through a positive energetic and structural balance alongside a negative waste balance.

History of Metabolism Research

Formal research into metabolism essentially began in the laboratory of French chemist Antone-Laurent de Lavoisier in the late 1700s. , A contemporary of Lavoisier’s, Joseph Priestly, had previously demonstrated that a mouse could not survive in a sealed flask if a flame had first burned in it; likewise, a flame could not burn in a flask in which a mouse had first breathed (and suffocated). , Lavoisier soon established that oxygen was the common limiting factor for both the survival of a burning flame and the survival of a breathing mouse. , By making this connection, Lavoisier discovered the fundamental overlap between chemistry and biology that sits at the core of bioenergetics: oxidation. ,

Prior to the use of ether as a surgical anesthetic in the mid-1800s, surgical procedures were performed on awake patients. By rendering patients unconscious, etherization allowed for a slower, more measured approach to operating. At around the same time, Joseph Lister pioneered the use of carbolic acid to prevent infection, and surgical mortality predictably began to decline. As surgical survival increased, the consequences of operations became more observable, leading to an increase in the understanding of recovery from tissue trauma and the surgical resection of organs. By the 1930s, David Cuthbertson had described the phenomenon of negative nitrogen balance after tissue trauma and argued that the losses were mostly due to muscle wasting.

Since then, it has become clear that tissue trauma, whether from surgical intervention or injury, induces a catabolic state driven by stress signaling ( Fig. 5.1 ). , , From the cell to the organism as a whole, the surgeon encounters severe responses to stress. Accordingly, the informed surgeon is well versed in the metabolic consequences of injury and illness, as well as in techniques for ameliorating those disruptions for the benefit of his or her patients.

Fig. 5.1, Simplified overview of metabolic pathways.

Cellular Bioenergetics

Adenosine triphosphate (ATP) is the most common currency of cellular bioenergetics by virtue of the chemical energy stored within the terminal phosphate bond. Rather than allowing the hydrolysis of ATP’s phosphate bond to occur spontaneously, the cell pairs the reaction with others, requiring large amounts of free energy in order to proceed, such as the activation and inactivation of enzymes. , ATP is synthesized from adenosine diphosphate (ADP) and phosphate via a reaction known as phosphorylation. , Multiple enzymes are capable of phosphorylating ADP to create ATP, with the most relevant to bioenergetics being ATP synthase, phosphoglycerate kinase, and pyruvate kinase. ,

Phosphorylation occurs under anaerobic conditions as part of glycolysis and in the presence of oxygen via oxidative phosphorylation. , A number of metabolic processes are linked together in order to support the process of oxidative phosphorylation, including glycolysis, amino acid catabolism, lipolysis, and the citric acid cycle ( Fig. 5.2 ). ,

Fig. 5.2, Overview of basic fuel substrate pathways. CoA , Coenzyme A; TCA , tricarboxylic acid.

The Citric Acid Cycle

The citric acid cycle, also called the tricarboxylic acid (TCA) cycle or the Krebs cycle, is an evolutionarily conserved series of enzymatic reactions that occur almost exclusively in the mitochondrial matrix ( Fig. 5.3 ). , , The proton motive force required to drive ATP synthesis is derived from the reducing capacity of flavin adenine dinucleotide (FADH 2 ) and nicotine adenine dinucleotide (NADH). These carriers donate the high-energy electrons that power the electron transport chain. , , Importantly, the TCA cycle only proceeds when oxygen delivery is high. When cellular oxygen availability is low, the cell instead ferments pyruvate to lactate, making pyruvate unavailable for conversion to acetyl-coenzyme A (CoA) and initiation of the TCA cycle. , , As not all cells contain mitochondria (e.g., red blood cells), a baseline concentration of lactate production is present at all times in the human body. , ,

Fig. 5.3, The citric acid (TCA/tricarboxylic acid/Krebs) cycle harnesses high energy electrons via the oxidation of pyruvate to power the electron transport chain, which generates the proton gradient that is used by ATP synthase to synthesize ATP.

Acetyl-CoA, derived from fatty acid oxidation, amino acid degradation, or glycolysis, provides the starting carbons in the form of an acetyl group attached to CoA. , , At the start of the cycle, citrate is synthesized by the enzyme citrate synthase from oxaloacetate and acetyl-CoA. , , Citrate is then converted to isocitrate by the enzyme aconitase. , , In the next step, NADH is regenerated from oxidized nicotinamide adenine dinucleotide (NAD+) and a molecule of CO 2 is released following the conversion of isocitrate to α-ketoglutarate by the enzyme isocitrate dehydrogenase. , , Next, α-ketoglutarate is converted to succinyl-CoA via the addition of a CoA and the removal of CO 2 by α-ketoglutarate dehydrogenase, regenerating another molecule of NADH. , , Succinyl-CoA becomes succinate via the action of succinyl-CoA synthetase. , ,

Succinate then is converted to fumarate via the action of succinic dehydrogenase, a reaction that also regenerates FADH 2 from FADH, which in turn reduces coenzyme Q. , , Importantly, succinate dehydrogenase is also Complex II in the electron transport chain and so marks a critical intersection between the TCA and the electron transport chain. , , Fumarate is converted to malate by the addition of water by fumarase, and malate is converted to oxaloacetate by malate dehydrogenase, regenerating a final molecule of NADH and resetting the cycle to begin again. , ,

Oxidative Phosphorylation

Oxidative phosphorylation is the process by which ATP synthesis is coupled to the movement of electrons through the mitochondrial electron transport chain and the associated consumption of oxygen. , , This process is the most efficient for ATP synthesis, generating approximately 36 ATP molecules per glucose molecule, compared to the two molecules of ATP generated during glycolysis. , ,

The free energy released by stepwise oxidation reactions between NADH, FADH 2 , and ubiquinol pumps protons from the mitochondrial matrix, across the mitochondrial inner membrane, and into the intermembrane space. , , This pumping action creates a tremendous proton concentration imbalance between the intermembrane space and the matrix. , , The potential energy stored in this proton gradient is then used to power ATP synthase phosphorylating ADP to generate ATP. , ,

The electron transport chain ( Fig. 5.3 ) involves the transfer of electrons from NADH and FADH 2 to ubiquinone (also called Coenzyme Q) through a series of four large protein complexes that reside in the mitochondrial inner membrane. , , Because the electrons begin the process at a high energy state and end the process in a low energy state, the electron transport chain entails the stepwise release of energy, which the protein complexes harness in order to pump protons from the mitochondrial matrix into the intermembrane space; each reaction in the electron transport chain represents a slight decrease in the energy of the electrons as they pass from complex to complex. , , An oxygen molecule sits at the end of the electron transport chain as the final electron acceptor, where it joins with two free protons to become water in a highly exothermic reaction. , , Without oxygen, the electrons in the electron transport chain cannot continue to fall down their potential energy gradient, and progression of electrons through the transport chain stops. , ,

In addition to the controlled transfer of electrons from complex to complex in the electron transport chain, thermodynamic factors at work within the mitochondria sometimes also favor the unintentional creation of reactive oxygen species, especially the superoxide anion (a molecule of oxygen with an extra electron). , , The superoxide anion is highly reactive, making it damaging to cells. Accordingly, mitochondria have an inbuilt manganese-dependent superoxide dismutase enzyme that immediately catalyzes the conversion of superoxide to the more manageable hydrogen peroxide. , , The accumulation of electrons at Complex I and Complex III that occurs when substrate delivery is high and ADP concentrations are low contributes most to superoxide creation. , , Intriguingly, by dissipating the proton gradient, the mitochondrial uncoupling proteins offload this pathogenic electron accumulation and thus decrease the creation of reactive oxygen species. ,

Fermentation

At low concentrations of cellular oxygen, oxidative phosphorylation ceases to function efficiently, yet the cell must continue to create ATP. , , Because ATP can be produced without oxygen via glycolysis, the cell must rely on the glycolytic pathway to support its energy needs. , , During glycolysis, glyceraldehyde-3-phosphate dehydrogenase reduces NAD+ to NADH when glyceraldehyde-3-phosphate is converted into 1,3-bisphosphoglycerate. , , Because NADH is not consumed by the electron transport chain under low-oxygen conditions, NADH concentrations begin to increase in the cell. , , In order to offload the accumulating NADH and regenerate NAD+ for use in the glycolytic pathway, the cell relies upon the fermentation of pyruvate into lactate by the lactate dehydrogenase enzyme, leading to the cellular accumulation of lactate. , , This process underlies blood lactate elevation observed with hypoperfusion during critical illness or with compartment syndrome. , , ,

The Lactic Acid (Cori) Cycle

In the first step of the Cori cycle ( Fig. 5.4 ), lactate created in peripheral tissues is transported in the bloodstream to the liver, where lactate dehydrogenase converts lactate into pyruvate for gluconeogenesis. , , The glucose thus produced is transported back into the bloodstream, where it can be delivered to cells in need of fuel substrates. , , If oxygen delivery has returned to normal, the pyruvate created by glycolysis will enter the TCA cycle—if oxygen delivery remains low, the cells will continue to ferment the pyruvate into lactate, causing the Cori cycle to repeat. , ,

Fig. 5.4, In the lactic acid (Cori) cycle, the lactate that is produced in peripheral tissues is converted back to glucose by the liver, then released into the circulation to support ongoing glycolysis in the periphery.

Glycolysis

In the process of glycolysis ( Fig. 5.5 ), glucose is converted to pyruvate via the sequential action of 10 enzymes at the cost of two molecules of ATP but with the generation of four molecules of ATP. , , Glycolysis has three rate-limiting steps that are the target of regulatory processes: (1) entry into the pathway catalyzed by hexokinase and glucokinase, (2) the irreversible conversion of fructose-6-phosphate into fructose-1,6-bisphosphate by phosphofructokinase, and (3) the final step in the pathway, the creation of pyruvate and ATP from phosphoenolpyruvate and ADP by pyruvate kinase. , ,

Fig. 5.5, Glycolysis and gluconeogenesis are the two opposing processes that sit at the core of glucose metabolism; where glycolysis makes energy available to the cell, gluconeogenesis can be used to export glucose into the circulation to make energy available to the body. Highlighted in gold are the points of regulation in gluconeogenesis, while the points of regulation in glycolysis are highlighted in blue .

Hexokinase and glucokinase

Glucose and other monosaccharides enter the cell via facilitated diffusion, a process mediated by the glucose transporter (GLUT) family of proteins that allows monosaccharides to cross the cell membrane driven primarily by their concentration gradients. , , Upon entry into the cell, hexokinase enzymes phosphorylate the molecules; because phosphorylated monosaccharides cannot pass through the GLUT, this modification effectively traps the monosaccharide inside the cell. , ,

Glucokinase is an isoform of hexokinase with two peculiarities: first, in contrast to hexokinase, the product of its reaction, glucose-6-phosphate, does not inhibit glucokinase, and second, it has a low binding affinity for glucose compared to the other hexokinase enzymes. , , These two differences mean that glucokinase activity varies only in response to glucose availability, allowing it to act as a sensor of fuel availability. , ,

Phosphofructokinase

Of the 10 reactions that comprise the glycolytic pathway, the first irreversible reaction is the conversion of fructose-6-phosphate to fructose-1,6-bisphosphate by phosphofructokinase. , , Because this step in the pathway is irreversible, it acts as a critical point of regulation—the activity of phosphofructokinase is sensitive to changes in energy availability due to inhibition by products of the glycolytic process and facilitation by excess glucose. , ,

Pyruvate kinase

The final step of glycolysis entails the removal of a phosphate from phosphoenolpyruvate and the subsequent phosphorylation of ADP to regenerate ATP. , , This irreversible reaction is catalyzed by pyruvate kinase. , , Pyruvate kinase is inhibited by its products and by signals from stress hormones like epinephrine and glucagon. , On the other hand, insulin drives pyruvate kinase activity, and thus glycolysis, forward. , ,

Gluconeogenesis

As with all processes in bioenergetics, glycolysis has an opposing process that essentially runs all of the glycolytic reactions in reverse—gluconeogenesis ( Fig. 5.5 ). , , Where as glycolysis breaks glucose and other monosaccharides down into pyruvate, gluconeogenesis takes various starting substrates, converts them to pyruvate or oxaloacetate, and then converts those substrates into glucose. , , While all cells in the human body can perform gluconeogenesis, only when the process occurs in the liver and kidneys can the resulting glucose be transported back into the bloodstream in order to defend against hypoglycemia. , , This is due to the tissue-specific expression of the glucose-6-phosphatase enzyme that dephosphorylates glucose-6-phosphate, allowing it to pass through the GLUT. , ,

The most important of the starting substrates for gluconeogenesis are lactate, fatty acids, and amino acids. , , Lactate enters the gluconeogenic pathway via the action of lactate dehydrogenase, an enzyme that converts lactate into pyruvate. , , Fatty acids that contain an odd number of carbons can be converted to pyruvate from propionyl-CoA via the combined action of propionyl-CoA carboxylase and the enzymes of the TCA cycle. Finally, some (but not all) amino acids can be converted into glucose and/or oxaloacetate. , ,

Glycogen

Glycogen is a large polysaccharide molecule composed of long chains of glucose molecules; it is found primarily in liver and skeletal muscle cells, where it serves as a storage form of glucose. , , Glycogen is synthesized by glycogen synthase, an enzyme that essentially polymerizes glucose in response to signals of increased energy availability, such as cellular concentrations of glucose-6-phoshpate and insulin. , , Glycogen can be broken down by glycogen phosphorylase, an enzyme that releases glucose-1-phosphate from the glycogen molecule—glycogen phosphorylase is activated by stress signals like epinephrine and glucagon. , ,

Glycogen is stored primarily in the liver and skeletal muscle cells. , , When a glucose-1-phosphate molecule is released from the glycogen molecule, it can be converted to glucose-6-phosphate by phosphoglucomutase. , , Glucose-6-phosphate can then be stripped of its phosphate by glucose-6-phosphatase and exported into the circulation in order to defend against hypoglycemia for approximately the first 24 hours after starvation. , , Where as liver cells possess high concentrations of the glucose-6-phosphatase enzyme and can release glucose molecules into the circulation, other glycogen-rich tissues like skeletal muscles have very low concentrations and cannot export meaningful amounts of glucose into the bloodstream. , ,

Fatty Acid Oxidation

In addition to monosaccharides, cells can use lipids as fuel substrates via the process of fatty acid oxidation, also called beta-oxidation. , , Although peroxisomes can degrade lipids via beta-oxidation, when the process is intended to fuel ATP synthesis, it takes place in the mitochondria. , , The long carbon chains of fatty acids are degraded two carbons at a time into acetyl groups, which are then attached to CoA, forming acetyl-CoA for entry into the TCA cycle. , , This process also regenerates FADH 2 and NADH in its own right, rendering the process of fatty acid oxidation very bioenergetically rewarding for the cell. , ,

Ketogenesis

The term ketone body generally refers to three substances: β-hydroxybutyrate, acetoacetate, and acetone. , , When carbohydrate availability is extremely low, such as during fasting or starvation when gluconeogenesis and glycogenolysis have been exhausted, the body will switch to a reliance on ketone bodies as fuel substrates. , , For example, while the brain normally uses glucose for energy, by the fourth day of fasting, the brain obtains about 70% of its energy from ketone bodies. , , Acetyl-CoA generated via fatty acid degradation would normally enter the TCA cycle; however, because oxaloacetate is depleted by ongoing gluconeogenesis during starvation, acetyl-CoA is instead used to form ketone bodies. , , The ketone bodies, in turn, can be broken down into pyruvate for use as fuel by the brain, heart, and muscles. , ,

Mitochondria

Mitochondria are double-membrane enveloped, energy-producing organelles that sit at the nexus of cellular energy homeostasis. Mitochondria generate ATP, the body’s main source of fuel, through oxidative phosphorylation and act as critical components of the cellular and organismal response to severe stress; in times of survivable cellular stress, the mitochondria are capable of buffering cellular calcium concentrations, while in times of lethal stress, they release cytochrome c into the cytoplasm, activating the caspase cascade, which leads to programmed cell death. On the organism level, mitochondria within the adrenal cortex synthesize the glucocorticoid and mineralocorticoid hormones that assist in adaptation to stress.

The mitochondria are of ancient and intriguing evolutionary origin: Although the details of the process are still debated, it is clear that, at some point in the distant past, a single-celled organism engulfed a mitochondrion-like cell and, rather than digest the protomitochondrion for food, established an endosymbiotic relationship. Since that time, the host and mitochondrion have peacefully coexisted, with each becoming ever-more dependent upon the other for survival. The evolutionary history of the mitochondrion is clear in its structure: it is the only organelle in eukaryotic cells that contains its own deoxyribonucleic acid (DNA), labeled mitochondrial DNA (mtDNA) to distinguish it from nuclear DNA. Furthermore, mitochondria undergo their own processes of fission and fusion independently of the cellular mitotic process.

Mitochondrial coupling control

When a mitochondrion is able to fully convert the potential energy of the proton gradient into ATP phosphorylation, it is said to be fully “coupled”—in other words, the synthesis of ATP is coupled to the proton motive force. , Various chemicals and proteins are able to interfere with mitochondrial electron transport chain coupling, leading to the proton-motive force dissipating as heat energy rather than the phosphorylation of ADP—these mitochondria are often referred to as “leaky.” , , Several proteins have recently been described that are capable of dissipating the proton gradient without ATP synthesis by allowing protons to bypass ATP synthase and diffuse directly into the mitochondrial matrix. The best understood of these proteins is called uncoupling protein 1, which serves to uncouple the diffusion of protons from the synthesis of ATP, thereby causing the mitochondria to become thermogenic and inefficient in times of stress or inflammation.

Brown Adipose Tissue

Brown adipose tissue (BAT) is a thermogenic tissue of mesenchymal lineage, named due to its characteristically dark appearance in histologic section due to abundant mitochondrial content and limited lipid droplets. Because BAT contains highly uncoupled and therefore inefficient mitochondria, each cell acts as an energy sink and therefore may be useful in humans as a potential treatment for obesity and diabetes.

Adult humans have very small depots of BAT, generally located above the clavicle, near the vertebrae, in the mediastinum, and around the kidney. BAT is characterized by abundant uncoupling protein expression, leading to mitochondria that are highly thermogenic due to elevated expression of uncoupling protein-1. Although the exact mechanism of mitochondrial thermogenesis is unclear, it is clearly linked to the dissipation of the proton gradient. For example, loss of the proton gradient causes the ATP synthase molecule to run in reverse, acting instead as a proton pump that attempts to restore the proton gradient at the expense of the highly exothermic hydrolysis of ATP. , Additionally, the dissipation of the proton gradient allows the electron transport chain to proceed at its maximal rate, resulting in increased consumption of oxygen by combustion with H 2 to yield H 2 O. ,

The BAT moniker is somewhat misleading, as BAT cells are thought to be derived from cells positive for the myogenic factor 5 surface marker, making them more closely related to muscle cells than white adipose tissue cells. Intriguingly, white adipose tissue cells are capable of acquiring BAT characteristics in response to stress in a process called “beiging” or “browning” that appears to be driven by peroxisome proliferator-activated receptor gamma coactivator 1α, the “master regulator” of mitochondrial biogenesis. For example, evidence of white adipose tissue browning can be found in patients after severe burns, which suggests that this process may contribute to the increase in nutritional needs during severe stress.

Maintenance of Cell Structure and Function

The structural and functional aspects of cells are composed of various combinations of proteins, lipids, carbohydrates, and nucleic acids. The synthesis and degradation of these cell components are under tight regulation, the loss of which can lead to severe cellular dysfunction.

Amino Acid Metabolism

Amino acids (also called peptides) are small organic molecules that consist of a carboxyl group, an amino group, and various side chains, the identity of which determines the behavior of the amino acid. , Although more than 500 amino acids can be found in nature, only 21 amino acids appear in human proteins. , There are a number of purposes in the body for amino acids beyond protein synthesis, including their use as precursors to neurotransmitters and nucleic acids or as fuel substrates (both as glucose and as ketones). ,

Proteinogenic amino acids

Human proteins are formed from long chains of amino acids that are sequentially linked via covalent peptide bonds between the carboxyl and amino groups; chains of amino acids are therefore called polypeptides . , Of the 21 amino acids that appear in human proteins ( Table 5.1 ), only 20 are directly coded for in the genetic code, with the 21st—selenocysteine—encoded by a stop codon that is differentially translated under specific circumstances. ,

Table 5.1
The proteinogenic amino acids.
Name Abbreviation
Essential amino acids Histidine HIS H
Isoleucine ILE I
Leucine LEU L
Lysine LYS K
Methionine MET M
Phenylalanine PHE F
Threonine THR T
Tryptophan TRP W
Valine VAL V
Conditionally essential amino acids Arginine ARG R
Cysteine CYS C
Glutamine GLN Q
Glycine GLY G
Proline PRO P
Tyrosine TYR Y
Nonessential amino acids Alanine ALA A
Asparagine ASN N
Aspartate ASP D
Glutamate GLU E
Selenocysteine SEC U
Serine SER S

Sources of amino acids

Of the 21 amino acids that are used to build human proteins, 12 can be synthesized by the body from various other substrates, while the remaining 9 must be consumed in the diet—these amino acids that must be taken in from external sources are called the “essential” amino acids. , , In addition to being classified by their source, amino acids can be classified by their structure, as in the case of the three branched-chain amino acids (BCAAs) that contain an aliphatic side chain: isoleucine, leucine, and valine. , , The BCAAs, leucine in particular, are an important component of nutritional status signaling in skeletal muscle; BCAAs in isolation stimulate muscle protein synthesis to the same degree that a complete mixture of all amino acids does, suggesting that the BCAAs signal the availability of amino acids for protein synthesis. , ,

Amino acids as fuel

Thirteen amino acids can be oxidized into glucose and as such are termed the “glucogenic” amino acids (alanine, arginine, asparagine, aspartate, cysteine, glutamate, glycine, histidine, methionine, proline, serine, valine, and glutamine), while five (isoleucine, phenylalanine, threonine, tryptophan, and tyrosine) can be converted to either ketones or glucose, and the final two (leucine and lysine) can only be converted into ketones. , ,

Alanine is converted to pyruvate and then glucose in the liver as part of the glucose-alanine cycle, a process with close similarity to the Cori cycle. The catabolism of BCAAs in skeletal muscle leads to the creation of toxic ammonium ions. In order to offload the accumulating ammonium ions, skeletal muscle cells synthesize alanine, which is transported to the liver for conversion back to glucose.

Amino acids as precursors to neurotransmitters

The human body uses the amino acids tryptophan, tyrosine, and phenylalanine as precursors to neurotransmitters. , Tryptophan is converted into serotonin, while tyrosine (itself a product of phenylalanine) is converted to all of the catecholamine neurotransmitters, including dopamine, epinephrine, and norepinephrine. Phenylalanine can be converted to tyrosine as well as phenylethylamine. ,

Toxic by-products of amino acid metabolism

Toxic ammonia, the ultimate result of amino acid and nucleotide breakdown, must be converted into water-soluble urea for excretion in the urine. While nitrogenous waste is formed throughout the body, the liver is the principal organ that converts wastes into urea. Because the body can ill afford to have the highly reactive ammonium ion freely circulating, the nitrogenous waste products are packaged into the amino acids glutamine and alanine for transport in the blood to the liver, where the amine group can be removed and converted into urea by the enzymes of the urea cycle. Patients with liver failure are at risk for developing hepatic encephalopathy, an accumulation of urea and other toxins in the bloodstream that interferes with normal neural function. Accordingly, caution must be exercised when managing the protein nutrition of liver failure patients.

The Urea Cycle

In the liver, mitochondrial and cytosolic enzymes work together to produce urea from ammonia in a process called the urea cycle ( Fig. 5.6 ). The urea cycle begins in the mitochondria with the transfer of ammonia from either glutamate or glutamine to a phosphorylated molecule of bicarbonate by the enzyme carbamoyl phosphate synthetase 1, creating carbamoyl phosphate. Carbamoyl phosphate then reacts with ornithine to form citrulline via the action of ornithine transcarbamylase, also in the mitochondria. Then, citrulline is transported out of the mitochondria and into the cytoplasm via the ornithine-citrulline transporter, where it reacts with aspartate to form argininosuccinate via the enzyme argininosuccinate synthetase. In turn, argininosuccinate is broken down to arginine and fumarate via the action of argininosuccinate lyase. Fumarate is then free to join the citric acid cycle, while arginine is degraded to urea and ornithine via the arginase enzyme. Ornithine is then transported back into the mitochondria via the ornithine-citrulline transporter, where the cycle can begin again.

Fig. 5.6, The urea cycle serves to convert potentially harmful amines to water soluble urea for excretion in the urine.

Lipid Metabolism

Cholesterol

Along with phospholipids, cholesterol is a critical element of cell membranes. Cholesterol is a steroid alcohol that consists of three cyclohexanes and a single cyclopentane. The starting substrate of the cholesterol biosynthesis pathway is acetyl-CoA and the key rate-limiting enzyme, β-hydroxy β-methylglutaryl-CoA. β-hydroxy β-methylglutaryl-CoA reductase is targeted by the statin class of cholesterol-lowering drugs. Because cholesterol can be fully synthesized by the human body, it has no dietary requirement.

The cholesterol molecule is the backbone of all steroid hormones in human physiology. The first (and rate-limiting) reaction to synthesize all steroid hormones is the conversion of cholesterol to pregnenolone by a cholesterol side chain cleavage enzyme. Additionally, while the sex steroids are synthesized in the endoplasmic reticulum, the final reactions of aldosterone, corticosterone, and cortisol biosynthesis also take place in the mitochondria. Where female sex steroid hormones are exclusively derived from the gonadal tissues, some intermediate androgens are synthesized within the adrenal glands and sent to the gonads for further processing. All mineralocorticoids and glucocorticoids are derived from the adrenal glands.

Fatty acids

Fatty acids are hydrophobic organic molecules that consist of aliphatic (hydrocarbon) chains bound to a carboxylic acid group. The length of their aliphatic chain and the location (if any) of double and/or triple carbon-carbon bonds are used to categorize fatty acids. Fatty acids that do not contain multiple bonds are termed “saturated” fatty acids, while those that contain at least one multiple bond are termed “unsaturated.” A fatty acid that has a single multiple bond is termed a “monounsaturated” fatty acid, while one that contains more than one multiple bond is termed a “polyunsaturated” fatty acid. When the first saturated bond occurs at the third carbon-carbon bond when counted from the tail (or “omega” end) of the aliphatic chain, the fatty acid is called an “omega-3” fatty acid. When the bond is at the sixth carbon-carbon bond when counted from the tail, the fatty acid is called an “omega-6” fatty acid. Notably, the omega-3 and omega-6 fatty acids cannot be synthesized in the human body, making them essential nutrients. ,

Omega-3 and omega-6 fatty acids are converted into eicosanoids, powerful but short-lived 20-carbon molecules that are synthesized in response to tissue injury and stress. , Cyclooxygenase (COX) and lipoxygenase are the best understood of the enzyme families that participate in these reactions. The prostaglandins, powerful and pleiotropic injury signaling molecules, are synthesized from arachidonic acid by COX-1 and COX-2 enzymes. The inhibition of COX-1 and COX-2 enzymes by nonsteroidal antiinflammatory medications leads to a reduction in pain and inflammation due to the decrease in prostaglandin synthesis at the site of injury. The lipoxygenase enzymes synthesize the proinflammatory leukotrienes, which are implicated in asthma. , ,

Phospholipids

Phospholipids are polar molecules that consist of a hydrophilic phosphorylated head group and a pair of hydrophobic fatty-acid tails, with one tail being fully saturated and the other tail being unsaturated. Because of their polarity, phospholipids spontaneously form lipid bilayers in water; accordingly, they serve as the primary component of the cell membrane. The common backbone of all phospholipids, phosphatidic acid, is synthesized in the cell from diacylglycerol, which in turn is synthesized from glycerol-6-phosphate and acyl-CoA by the sequential actions of glycerol-3-phosphate acyltransferase and acylglycerol-3-phosphate acyltransferase.

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