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Chapter: Biochemistry : Introduction to Metabolism and Glycolysis

Most pathways can be classified as either catabolic (degrade complex molecules to a few simple products) or anabolic (synthesize complex end products from simple precursors).


Most pathways can be classified as either catabolic (degrade complex molecules to a few simple products) or anabolic (synthesize complex end products from simple precursors). Catabolic reactions also capture chemical energy in the form of ATP from the degradation of energy-rich molecules. Anabolic reactions require energy, which is generally provided by the hydrolysis of ATP. The rate of a metabolic pathway can respond to regulatory signals such as allosteric activators or inhibitors that arise from within the cell. Signaling between cells provides for the integration of metabolism. The most important route of this communication is chemical signaling (for example, by hormones or neurotransmitters). Second messenger molecules transduce a chemical signal (hormone or neurotransmitter) to appropriate intracellular responders. Adenylyl cyclase is a cell membrane enzyme that synthesizes cyclic AMP (cAMP) in response to chemical signals, such as the hormones glucagon and epinephrine. Following binding of a hormone to its cell-surface receptor, a GTP-dependent regulatory protein (G protein) is activated that, in turn, activates adenylyl cyclase. The cAMP produced activates a protein kinase, which phosphorylates a cadre of enzymes, causing their activation or deactivation. Phosphorylation is reversed by protein phosphatases. Aerobic glycolysis, in which pyruvate is the end product, occurs in cells with mitochondria and an adequate supply of oxygen (Figure 8.25) . Anaerobic glycolysis, in which lactic acid is the end product, occurs in cells that lack mitochondria and in cells deprived of sufficient oxygen. Glucose is transported across membranes by one of 14 glucose transporter isoforms (GLUTs). GLUT-1 is abundant in erythrocytes and the brain, GLUT-4 (which is insulin dependent) is found in muscle and adipose tissue, and GLUT-2  is found in the liver, kidney, and β cells of the pancreas. The conversion of glucose to pyruvate (glycolysis; Figure 8.25) occurs in two stages: an energy– investment phase in which phosphorylated intermediates are synthesized at the expense of ATP, and an energy-generation phase, in which ATP is produced. In the energy-investment phase, glucose is phosphorylated by hexokinase (found in most tissues) or glucokinase (a hexokinase found in liver cells and the β cells of the pancreas). Hexokinase has a high affinity (low Km) and a low Vmax for glucose and is inhibited by glucose 6-phosphate. Glucokinase has a high Km and a high Vmax for glucose. It is indirectly inhibited by fructose 6-phosphate and activated by glucose. The transcription of the gene for glucokinase is enhanced by insulin. 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 phosphofructokinase-2 (PFK-2) is activated by insulin, 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 these reactions, four ATP and two NADH are produced from ADP and NAD+. 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 hormonally activated by insulin and inhibited in the liver by glucagon via the cAMP pathway. PK deficiency accounts for the majority of all inherited defects in glycolytic enzymes. Effects are restricted to erythrocytes and present as mild to severe chronic, nonspherocytic hemolytic anemia. In anaerobic glycolysis, NADH is reoxidized to NAD+ by the conversion of pyruvate to lactate. This occurs in cells, such as erythrocytes, that have few or no 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 when there is a collapse of the circulatory system or when an individual is in shock. Pyruvate can be 1) oxidatively decarboxylated by pyruvate dehydrogenase, producing acetyl coenzyme A; 2) carboxylated to oxaloacetate (a tricarboxylic acid cycle intermediate) by pyruvate carboxylase; or 3) reduced by microorganisms to ethanol by pyruvate decarboxylase.

Figure 8.25 Key concept map for glycolysis. NAD(H) = nicotinamide adenine dinucleotide; cAMP = cyclic adenosine monophosphate; CoA = coenzyme A; TCA = tricarboxylic acid.

Study Questions

Choose the ONE best answer.


8.1 Which of the following best describes the activity level and phosphorylation state of the listed hepatic enzymes in an individual who consumed a carbohydrate-rich meal about an hour ago? PFK-1 = phosphofructokinase-1; PFK-2 = phosphofructokinase-2; P = phosphorylated.

Correct answer = C. In the period immediately following a meal, blood glucose levels and hepatic uptake of glucose increase. The glucose is phosphorylated to glucose 6-phosphate and used in glycolysis. In response to the rise in blood glucose, the insulin-to-glucagon ratio increases. As a result, the kinase domain of PFK-2 is dephosphorylated and active. Its product, fructose 2,6-bisphosphate, allosterically activates PFK-1. (PFK-1 is not covalently regulated.) Active PFK-1 produces fructose 1,6-bisphosphate that is a feedforward activator of pyruvate kinase. Hepatic pyruvate kinase is covalently regulated, and the rise in insulin favors dephosphorylation.


8.2 Which of the following statements is true for anabolic pathways only?

A. Their irreversible (nonequilibrium) reactions are regulated.

B. They are called cycles if they regenerate an intermediate.

C. They are convergent and generate a few simple products.

D. They are synthetic and require energy.

E. They typically require oxidized coenzymes.

Correct answer = D. Anabolic processes are synthetic and energy requiring (endergonic). Statements A and B apply to both anabolic and catabolic processes, whereas C and E apply only to catabolic processes.


8.3 Compared with the resting state, vigorously contracting skeletal muscle shows:

A. decreased AMP/ATP ratio.

B. decreased levels of fructose 2,6-bisphosphate.

C. decreased NADH/NAD+ ratio.

D. increased oxygen availability.

E. increased reduction of pyruvate to lactate.

Correct answer = E. Vigorously contracting muscle shows an increase in the reduction of pyruvate to lactate compared with resting skeletal muscle. The levels of adenosine monophosphate (AMP) and reduced nicotinamide adenine dinucleotide (NADH) increase, whereas change in the concentration of fructose 2,6-bisphosphate is not a key regulatory factor in skeletal muscle. The rise in the NADH to NAD+ ratio exceeds the oxidative capacity of the respiratory chain.


8.4 Glucose uptake by:

A. liver cells is through facilitated diffusion involving a glucose transporter.

B. intestinal mucosal cells requires insulin.

C. brain cells is through energy-requiring (active) transport.

D. most cells is through simple diffusion up a concentration gradient.

Correct answer = A. Glucose uptake in the liver, brain, muscle, and adipose tissue is down a concentration gradient, and the diffusion is facilitated by tissue-specific glucose transporters (GLUTs). In adipose and muscle, insulin is required for glucose uptake. Moving glucose against a concentration gradient requires energy, and is seen with sodium-dependent glucose transporter-1 (SGLT-1) of intestinal mucosal cells.


8.5 Given that the Km of glucokinase for glucose is 10 mM whereas that of hexokinase is 0.1 mM, which isozyme will more closely approach Vmax at the normal blood glucose concentration of 5 mM?

Correct answer = Hexokinase. Km is that substrate concentration that gives 1⁄2 Vmax. When blood glucose concentration is 5 mM, hexo-kinase (Km = 0.1 mM) will be saturated, but glucokinase (K m = 10 mM) will not.


8.6 In patients with whooping cough, Gαi is inhibited. How does this lead to a rise in cyclic AMP?

 Liganded G proteins of the Gαi type inhibit adenylyl cyclase. If Gαi is inhibited by toxin, adenylyl cyclase production of cyclic adenosine monophosphate (cAMP) is inappropriately activated.


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