Citric Acid Cycle

Functions

Production of energy 

• Direct production of guanosine triphosphate (GTP) (equivalent to adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs triphosphate [ATP])
• NADH + H⁺ and FADH₂ then produce ATP within the respiratory chain. 

Amphibolic center

The citric acid cycle provides precursors for many catabolic and anabolic processes.

• Precursors for amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids:
  • Alpha-ketoglutarate for glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids
  • Oxaloacetate for aspartate Aspartate One of the non-essential amino acids commonly occurring in the l-form. It is found in animals and plants, especially in sugar cane and sugar beets. It may be a neurotransmitter. Synthesis of Nonessential Amino Acids
• Succinyl-CoA is crucial for the synthesis Synthesis Polymerase Chain Reaction (PCR) of porphyrins or heme.
• Citrate is needed for the synthesis Synthesis Polymerase Chain Reaction (PCR) of fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance and cholesterol Cholesterol The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. Cholesterol Metabolism.
• Oxaloacetate is a substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes for gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis.

Reactions, Yield, and Energy Balance

Two main substrates: acetyl-CoA and oxaloacetate

• Acetyl-CoA from the beta-oxidation of fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance and glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis
  • Pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis dehydrogenase produces acetyl-CoA from pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis.
• Oxaloacetate from regeneration Regeneration The physiological renewal, repair, or replacement of tissue. Wound Healing within the Krebs cycle or from pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis
  • Pyruvate carboxylase Pyruvate carboxylase A biotin-dependent enzyme belonging to the ligase family that catalyzes the addition of carbon dioxide to pyruvate. It is occurs in both plants and animals. Gluconeogenesis produces oxaloacetate from pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis and CO₂.

Steps:
Acetyl-CoA (C2) + oxaloacetate (C4) → Citrate (C6) → Isocitrate (C6) → α-Ketoglutarate (C5) → Succinyl-CoA (C4) → Succinate (C4) → Fumarate (C4) → Malate (C4) → Oxaloacetate (C4)
Mnemonic device: Citrate Is Krebs’ Starting Substrate For Making Oxaloacetate

Notable reactions:

• Irreversible:
  • Acetyl-CoA + oxaloacetate → citrate via citrate synthase
  • Isocitrate → α-ketoglutarate via isocitrate dehydrogenase
  • α-ketoglutarate → succinyl-CoA via α-ketoglutarate dehydrogenase
• Succinate dehydrogenase: only enzyme of the Krebs cycle that is anchored to the inner membrane of the mitochondrion
• α-ketoglutarate dehydrogenase: requires 5 cofactors
  • Thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies pyrophosphate
  • Lipoic acid
  • Coenzyme A
  • FAD
  • NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺

Yield:
3 NADH + H⁺ + 1 FADH₂ + 1 GTP + 2 CO₂ per acetyl-CoA (x 2 per glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance)

Energy balance:
7.5 ATP (3 NADH + H⁺) + 1.5 ATP (1 FADH₂) + 1 ATP (1 GTP) = 10 ATP per acetyl-CoA (x 2 per glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance)

Regulation

Clinical Relevance

The following process is stimulated by the tricarboxylic acid (TCA) cycle:

• Ketogenesis Ketogenesis Ketone Body Metabolism: the synthesis Synthesis Polymerase Chain Reaction (PCR) of ketone bodies Ketone bodies The metabolic substances acetone; 3-hydroxybutyric acid; and acetoacetic acid (acetoacetates). They are produced in the liver and kidney during fatty acids oxidation and used as a source of energy by the heart, muscle and brain. Ketone Body Metabolism from acetyl-CoA. Ketogenesis Ketogenesis Ketone Body Metabolism is caused by prolonged starvation, diabetic ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis, and alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome. The inhibition of the TCA cycle leads to a rise in acetyl-CoA levels, which directly stimulates ketogenesis Ketogenesis Ketone Body Metabolism.

The following conditions inhibit the TCA cycle:

• Hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis: a condition defined by an excess of ammonia Ammonia A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. Note that the aqueous form of ammonia is referred to as ammonium hydroxide. Acid-Base Balance in the blood. It may be acquired ( liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy disease) or hereditary ( urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle cycle enzyme deficiencies). In hyperammonemia Hyperammonemia Elevated level of ammonia in the blood. It is a sign of defective catabolism of amino acids or ammonia to urea. Cirrhosis, the level of α-ketoglutarate rises, inhibiting the TCA cycle. It presents as asterixis Asterixis Hepatic Encephalopathy, slurring of speech, somnolence, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, cerebral edema Cerebral edema Increased intracellular or extracellular fluid in brain tissue. Cytotoxic brain edema (swelling due to increased intracellular fluid) is indicative of a disturbance in cell metabolism, and is commonly associated with hypoxic or ischemic injuries. An increase in extracellular fluid may be caused by increased brain capillary permeability (vasogenic edema), an osmotic gradient, local blockages in interstitial fluid pathways, or by obstruction of CSF flow (e.g., obstructive hydrocephalus). Increased Intracranial Pressure (ICP), and blurry vision Vision Ophthalmic Exam. 
• Thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies deficiency: a condition that occurs due to malnutrition Malnutrition Malnutrition is a clinical state caused by an imbalance or deficiency of calories and/or micronutrients and macronutrients. The 2 main manifestations of acute severe malnutrition are marasmus (total caloric insufficiency) and kwashiorkor (protein malnutrition with characteristic edema). Malnutrition in children in resource-limited countries and/or alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome, which inhibits the enzyme α-ketoglutarate dehydrogenase via a lack of one of its cofactors ( thiamine Thiamine Also known as thiamine or thiamin, it is a vitamin C12H17N4OSCl of the vitamin B complex that is essential to normal metabolism and nerve function and is widespread in plants and animals Water-soluble Vitamins and their Deficiencies). This leads to the accumulation of glutamate Glutamate Derivatives of glutamic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that contain the 2-aminopentanedioic acid structure. Synthesis of Nonessential Amino Acids, leading to Wernicke’s encephalopathy Encephalopathy Hyper-IgM Syndrome. It presents as a triad of confusion, ophthalmoplegia Ophthalmoplegia Paralysis of one or more of the ocular muscles due to disorders of the eye muscles, neuromuscular junction, supporting soft tissue, tendons, or innervation to the muscles. Orbital and Preseptal Cellulitis, and ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia.
• Diabetic ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis: a condition primarily seen in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with type I diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus, which is caused by insufficient insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin levels. It presents with hyperglycemia Hyperglycemia Abnormally high blood glucose level. Diabetes Mellitus, polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation, polydipsia Polydipsia Excessive thirst manifested by excessive fluid intake. It is characteristic of many diseases such as diabetes mellitus; diabetes insipidus; and nephrogenic diabetes insipidus. The condition may be psychogenic in origin. Diabetes Insipidus, nausea Nausea An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. Antiemetics, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, and volume depletion Volume depletion Volume status is a balance between water and solutes, the majority of which is Na. Volume depletion refers to a loss of both water and Na, whereas dehydration refers only to a loss of water. Volume depletion can be caused by GI losses, renal losses, bleeding, poor oral Na intake, or third spacing of fluids. Volume Depletion and Dehydration. It can inhibit the TCA cycle by lowering the levels of oxaloacetate.
• Alcohol use disorder Alcohol use disorder Alcohol is one of the most commonly used addictive substances in the world. Alcohol use disorder (AUD) is defined as pathologic consumption of alcohol leading to impaired daily functioning. Acute alcohol intoxication presents with impairment in speech and motor functions and can be managed in most cases with supportive care. Alcohol Use Disorder: Alcoholism Alcoholism A primary, chronic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. The disease is often progressive and fatal. It is characterized by impaired control over drinking, preoccupation with the drug alcohol, use of alcohol despite adverse consequences, and distortions in thinking, most notably denial. Each of these symptoms may be continuous or periodic. Wernicke Encephalopathy and Korsakoff Syndrome is a level of alcohol consumption that exceeds the sociocultural standard. The condition is marked by mental and physical addiction Addiction Substance use disorders are a significant cause of morbidity and mortality, especially among adolescents and young adults. A substance-related and addictive disorder is the continued use of a substance despite harmful consequences; these include significant impairment to one’s health or relationships or failure to fulfill major responsibilities at work, school, or home because of substance use. Substance-Related and Addictive Disorders with an irresistible desire for alcohol and tolerance Tolerance Pharmacokinetics and Pharmacodynamics of the drug. It can inhibit the TCA cycle by causing a rise in the NADH/ NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway⁺ ratio.