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Enzymes catalyzing irreversible reactions in metabolic pathways are potential control sites. In glycolysis, these enzymes are 1. Hexokinase 2. Phosphofructokinase 3. Pyruvate kinase Phosphofructokinase is the key regulator of glycolysis in mammals. The enzyme is allosterically inhibited by ATP and allosterically stimulated by AMP. When ATP needs are great, adenylate kinase generates ATP from 2 ADP. AMP then becomes the signal for the low-energy state. Low pH augments the inhibitory effect of ATP. Production of lactate resulting from anaerobic utilization of glucose in muscle reduces pH. Hexokinase is allosterically inhibited by glucose 6-phosphate. Hexokinase- phosphofructokinase communication A rise in glucose 6-phosphate concentration is a means by which phosphofructokinase communicates with hexokinase. When phosphofructokinase is inactive, the concentration of fructose 6-phosphate rises. In turn, the level of glucose 6-phosphate rises because it is in equilibrium with fructose 6-phosphate. Hence, the inhibition of phosphofructokinase leads to the inhibition of hexokinase. Hexokinase is allosterically inhibited by glucose 6-phosphate. Pyruvate kinase is inhibited by the allosteric signals ATP and alanine, and stimulated by fructose 1, 6-bisphosphate, the product of the phosphofructokinase reaction. In muscle, glycolysis is regulated to meet the energy needs of contraction. Conversion of F-6-P to F-1,6-BP is the committed step in glycolysis The key regulators of phosphofructokinase in liver are citrate, which reports on the status of the citric acid cycle, and fructose 2, 6-bisphosphate. Citrate inhibits phosphofructokinase whereas fructose 2,6-bisphosphate is a powerful activator. Citric acid (coveys abundant intermediates) Hexokinase is an allosteric enzyme in the liver as it is in muscle. The enzyme primarily responsible for phosphorylating glucose in the liver is glucokinase. Glucokinase is active only after a meal, when blood-glucose levels are high. The low affinity glucokinase in liver ensures that glucose is utilized for anabolic purposes only after its need for energy production, in brain and muscle, is met. Pyruvate kinase in the liver is regulated allosterically as it is in muscle. However, liver pyruvate kinase is also regulated by covalent modification. Low blood glucose leads to the phosphorylation and inhibition of liver pyruvate kinase. Five glucose transporters, termed GLUT1-5, facilitate the movement of glucose across the cell membrane. Rapidly growing tumors obtain ATP by metabolizing glucose to lactate even in the presence of oxygen, a process termed aerobic glycolysis or the Warburg effect. When patients are infused with a non-metabolizable analog of glucose, tumors are readily visualized by tomography. The transcription factor hypoxia-inducible transcription factor 1 (HIF-1) facilitates aerobic glycolysis. Exercise training also stimulates HIF-1, which enhances the ability to generate ATP anaerobically and stimulates new blood vessel growth. Gluconeogenesis is the synthesis of glucose from noncarbohydrate precursors. The major precursors for gluconeogenesis are lactate, amino acids, and glycerol. The major site of gluconeogenesis is the liver, although some gluconeogenesis can occur in the kidney. Gluconeogenesis is especially important during fasting or starvation, as glucose is the primary fuel for the brain and the only fuel for red blood cells. The three irreversible steps in glycolysis must be bypassed in gluconeogenesis. The formation of phosphoenolpyruvate from pyruvate requires two enzymes: pyruvate carboxylase and phosphoenolpyruvate carboxykinase. Pyruvate carboxylase uses the vitamin biotin as a cofactor. The formation of oxaloacetate by pyruvate carboxylase occurs in three stages. 1. The biotin carboxylase domain catalyzes the formation carboxyphosphate. 2. The carboxylase then transfers the CO2 to the biotin carboxyl carrier protein (BCCP). 3. The BCCP carries the activated CO2 to the pyruvate carboxylase domain, where the CO2 is transferred to pyruvate to form oxalacetate. Acetyl CoA is a required cofactor for carboxylation of biotin. Pyruvate carboxylase functions as a tetramer composed of four identical subunits, and each subunit consists of four domains. The biotin carboxylase domain (BC) catalyzes the formation of carboxyphosphate and the subsequent attachment of CO2 to the second domain, the biotin carboxyl carrier protein (BCCP), the site of the covalently attached biotin. Once bound to CO2, BCCP leaves the biotin carboxylase active site and swings almost the entire length of the subunit (≈75Å) to the active site of the pyruvate carboxylase domain (PC), which transfers the CO2 to pyruvate to form oxaloacetate. BCCP in one subunit interacts with the active sites on an adjacent subunit. The fourth domain (PT) facilitates the formation of the tetramer. The formation of oxaloacetate by pyruvate carboxylase occurs in the mitochondria. Oxaloacetate is reduced to malate and transported into the cytoplasm, where it is reoxidized to oxaloacetate with the generation of cytoplasmic NADH. PEP is then synthesized from oxaloacetate by phosphoenolpyruvate carboxykinase. The sum of the reactions catalyzed by pyruvate carboxylase and phosphoenolpyruvate carboxylase is Phosphoenolpyruvate is metabolized by the enzymes of glycolysis in the reverse direction until the next irreversible step, the hydrolysis of fructose 1,6-bisphosphate. The enzyme catalyzing this reaction is fructose 1,6-bisphosphatase, an allosteric enzyme. The generation of free glucose, which occurs essentially only in liver, is the final step in gluconeogenesis. Glucose 6-phosphate is transported into the lumen of the endoplasmic reticulum. Glucose 6-phosphatase, an integral membrane protein on the inner surface of the endoplasmic reticulum, catalyzes the formation of glucose from glucose 6-phosphate. Gluconeogenesis and glycolysis are regulated so that within a cell, one pathway is relatively inactive whereas the other is highly active. The rationale for reciprocal regulation is that glycolysis will predominate when glucose is abundant, and gluconeogenesis will be highly active when glucose is scarce. The interconversion of fructose 1, 6-bisphosphate and fructose 6-phosphate is a key regulatory site. Additionally, glycolysis and gluconeogenesis are reciprocally regulated at the interconversion of phosphoenolpyruvate and pyruvate. If ATP is required, glycolysis predominates. If glucose is required, gluconeogenesis is favored. In liver, the rates of glycolysis and gluconeogenesis are adjusted to maintain bloodglucose levels. The key regulator of glucose metabolism in liver is fructose 2, 6-bisphosphate. Fructose 2, 6-bisphosphate stimulates phosphofructokinase and inhibits fructose 1, 6-bisphosphatase. The kinase that synthesizes fructose 2, 6-bisphosphate and the phosphatase that hydrolyzes this molecule are located on the same polypeptide chain. Such an arrangement is called a bifunctional enzyme. Phosphorylation of the bifunctional enzyme activates the phosphatase activity and inhibits the kinase activity. Substrate cycles can enhance the regulation of flux down a metabolic pathway. Muscle and liver display inter-organ cooperation in a series of reactions called the Cori cycle. Lactate produced by muscle during contraction is released into the blood. Liver removes the lactate and converts it into glucose, which can be released into the blood. The second part of glycolysis, the metabolism of trioses, is common to both glycolysis and gluconeogenesis. The four enzymes catalyzing the metabolism of these trioses are present in all species. In contrast, the enzymes of the first part of glycolysis, the metabolism of hexoses, are not nearly as conserved. The common part of the two pathways may be the oldest part, to which other reactions were added during the course of evolution.