Metabolism and Glycolysis

Most pathways can be classified as either catabolic (degrade complex molecules to a few simple products with ATP production) or anabolic (synthesize complex end products from simple precursors with ATP hydrolysis). The rate of a metabolic pathway can respond to regulatory signals such as intracellular allosteric activators or inhibitors. Intercellular signaling provides for the integration of metabolism. The primary route of this communication is chemical signaling (for example, by hormones or neurotransmitters). Second messenger molecules transduce a chemical signal (hormone or neurotransmitter binding) to appropriate intracellular responders. Adenylyl cyclase (AC) is a cell membrane enzyme that synthesizes cyclic adenosine monophosphate (cAMP) in response to chemical signals, such as the hormones glucagon and epinephrine.
Following binding of a hormone to its cell-surface G protein–coupled receptor, a guanosine triphosphate–dependent regulatory protein (G protein) is activated that, in turn, activates AC. The cAMP produced activates protein kinase A, which phosphorylates a variety of enzymes, causing their activation or deactivation. Phosphorylation is reversed by phosphatases. Aerobic glycolysis, in which pyruvate is the end product, occurs in cells with mitochondria and an adequate supply of oxygen ([O2], Fig. 1). Anaerobic glycolysis, in which lactic acid is the end product, occurs in cells that lack mitochondria and in cells deprived of sufficient O2.
Glucose is passively transported across membranes by 1 of 14 glucose transporter (GLUT) isoforms. GLUT-1 is abundant in RBC and the brain, GLUT-4 (which is insulin dependent) in muscle and adipose tissue, and GLUT-2 in the liver, kidneys, and pancreatic β cells. The oxidation of glucose to pyruvate (glycolysis, see Fig. 1) occurs through an energyinvestment phase in which phosphorylated intermediates are synthesized at the expense of ATP and an energy-generation phase in which ATP is produced by substrate-level phosphorylation. In the energy-investment phase, glucose is phosphorylated by hexokinase (found in most tissues) or glucokinase (a hexokinase found in liver cells and pancreatic β cells).
Hexokinase has a high affinity (low _Km) and a low maximal velocity (Vmax) for glucose and is inhibited by glucose 6-phosphate. Glucokinase has a high K_m and a high V_max for glucose. It is regulated indirectly by fructose 6-phosphate (inhibits) and glucose (activates) via glucokinase regulatory protein. Glucose 6-phosphate is isomerized to fructose 6-phosphate, which is phosphorylated to fructose 1,6-bisphosphate by phosphofructokinase-1 (PFK-1). This enzyme is allosterically inhibited by ATP and citrate and activated by AMP. Fructose 2,6-bisphosphate, whose synthesis by bifunctional phosphofructokinase-2 (PFK-2) is increased in the liver by insulin and decreased by glucagon, is the most potent allosteric activator of PFK-1. A total of two ATP are used during this phase of glycolysis. Fructose 1,6-bisphosphate is cleaved to form two trioses that are further metabolized by the glycolytic pathway, forming pyruvate. During this phase, four ATP and two nicotinamide adenine dinucleotide (NADH) are produced per glucose molecule. The final step in pyruvate synthesis from phosphoenolpyruvate is catalyzed by pyruvate kinase (PK). This enzyme is allosterically activated by fructose 1,6-bisphosphate, and the hepatic isozyme is inhibited covalently by glucagon via the cAMP pathway. PK deficiency accounts for the majority of all inherited defects in glycolytic enzymes. Effects are restricted to RBC and present as mild-tosevere chronic, nonspherocytic hemolytic anemia.

Glycolytic gene transcription is enhanced by insulin and glucose. In anaerobic glycolysis, NADH is reoxidized to NAD+ by the reduction of pyruvate to lactate via lactate dehydrogenase. This occurs in cells such as RBC that lack mitochondria and in tissues such as exercising muscle, where production of NADH exceeds the oxidative capacity of the respiratory chain. Elevated concentrations of lactate in the plasma (lactic acidosis) occur with circulatory system collapse or shock. Pyruvate also can be 1) oxidatively decarboxylated to acetyl CoA by pyruvate dehydrogenase, 2) carboxylated to oxaloacetate (a TCA cycle intermediate) by pyruvate carboxylase, or 3) reduced to ethanol by microbial pyruvate decarboxylase.

Figure 1:  Key concept map for glycolysis. NAD(H) = nicotinamide adenine dinucleotide; cAMP = cyclic adenosine monophosphate; CoA = coenzyme A; TCA = tricarboxylic acid; CO2 = carbon dioxide.

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