Ferchmin Review 2019 If you find errors, please, let me know.

Use this sketch to follow the movement of labeled carbons from one metabolic pathway to another. A question you could find later in this course might be: Starting fatty acid synthesis from glucose-3-C14. In which positions of a newly synthesized fatty will the C14 be found?

Disease Deficiency Subject Hereditary fructose intolerance   Deficiency Subject Hereditary fructose intolerance Fructose-1-phosphate aldolase (aldolase B) deficiency fructose metabolism Galactosemia (mild form) Galactokinase deficiency galactose metabolism Galactosemia (severe form) Hexose-1-phosphate uridylyltransferase deficiency Galactosemia Type III. UDP-glucose-4-epimerase Lactose intolerance (milk intolerance) Intestinal lactase deficiency lactose metabolism Hypoglycemia secondary to ethanol ingestion Cytoplasmic NAD depletion Gluconeogenesis Von Gierke disease (glycogen storage disease Glucose-6-phosphatase deficiency glycogen metabolism Pompe's disease Lysosomal acid maltase deficiency Cori's disease Glycogen debranching enzyme deficiency Andersen's disease Glycogen branching enzyme deficiency McArdle's Disease Muscle glycogen phosphorylase deficiency glycogen storage disease Tarui disease Muscle phosphofructokinase deficiency Primaquine-induced hemolytic anemia Glucose-6-phosphate dehydrogenase deficiency Pentose phosphate pathway Beriberi Chronic thiamine deficiency vitamins Wernicke encephalopathy in a chronic alcoholic. Acute thiamine deficiency The buildup of a phosphorylated monosaccharide in the liver will cause hypophosphatemia, hypoglycemia, liver damage, and as a result of the injury, jaundice (ictericia in Spanish). H2 in the exhaled air is an indication of generic sugar intolerance. Lactose intolerance, after weaning is normal in mammals unless genetically adapted to a dairy diet. Glucose-6-phosphate dehydrogenase deficiency is caused by an unstable enzyme that degrades with time and metabolic stress. Therefore, old erythrocytes will have a deficiency of the glucose-6-phosphate dehydrogenase, low NADPH followed by hemolytic anemia. However, as new immature erythrocytes enter circulation, the anemia stops.

Which of the following participates directly in the synthesis of glucosamine-6-phosphate from fructose-6-phosphate?   a. Glutamine:fructose-6-phosphate transaminase b. Glucose-6-phosphate dehydrogenase c. Phosphofructokinase-2 d. Glycine e. ATP

Different cell types regulate their plasma membrane transport of glucose differently. Some cell types display insulin-dependent transport of glucose while others transport glucose independent of insulin levels. In the table below, insulin-dependent membrane transport of glucose is indicated by (+) and glucose transport independent of insulin is indicated by (–). Which answer is correct for the five cell types shown?

40. Which of the following processes can produce net gluconeogenesis in humans? a. synthesis of glucose from glucogenic α-amino acids b. formation of glucose from galactose synthesis of glucose from acetylCoA d. synthesis of glucose from ethanol e. release of glucose from glycogen

41. Insulin binds to which of the following molecules on the plasma membrane of its target cells? a. a membrane receptor that transfers insulin into the nucleus where insulin directly modulates gene expression b. a membrane receptor that activates adenylate cyclase and increase the cytoplasmic cyclic AMP level c. a membrane receptor that has protein tyrosine kinase activity in its cytosolic domain a membrane receptor that opens Na+ and Ca2+ channels through the plasma membrane e. the GluT4 membrane glucose transporter

The crossover theorem states that: the variations of the concentrations of the metabolites before and after an enzyme which is a control point have different signs. In glycolysis, if you inhibit any (preferentially) regulatory enzyme the “up stream” metabolites will increase and the “down stream” will decrease. A more “garden variety” illustration of the crossover theorem is that when you step on a water hose the water “up stream” of your foot will expand the hose and the “down stream” hose will deflate. When you remove your foot from the hose the flow will abruptly increase. The Mister in the picture already tested the crossover theorem, therefore, you do not have to repeat the test.

Glycolytic pathway defects are autosomal recessive red blood cell metabolic disorders that cause hemolytic anemia. The most common defect is: Pyruvate kinase deficiency Other defects that cause hemolytic anemia include deficiencies of Erythrocyte hexokinase Glucose phosphate isomerase Phosphofructokinase

b. erythrocytes with abnormally low affinity for oxygen. 43. The blood of a patient who has an inherited deficiency of pyruvate kinase shows: a. erythrocytes with abnormally low levels of 2,3-bisphosphoglycerate (BPG). b. erythrocytes with abnormally low affinity for oxygen. c. erythrocytes with abnormally high affinity for oxygen. d. erythrocytes with abnormally high levels of ATP. e. a high concentration of plasma lactate. There are

42. High cytoplasmic levels of citrate reduce the activity of which of the following pathways? the pentose phosphate pathway b. glycogenesis c. gluconeogenesis d. fatty acid synthesis e. glycolysis

49. With glycogen as the source of glucose, the oxidation of 1 mole of glucose by anaerobic glycolysis produces a theoretical net maximum yield of: a. 3 moles of lactate, 2 moles of NADH and 3 moles of ATP. b. 2 moles of pyruvate, 4 moles of NADH and 2 moles of ATP. c. 2 moles of pyruvate, 3 moles of NAD and 4 moles of ATP. d. 2 moles of lactate and 3 moles of ATP. e. 2 moles of lactate and 2 moles of ATP.

50. An increased concentration of AMP in muscle cells activates which of the following enzymes? a. fructose-1,6-bis-1-phosphatase b. glycogen synthase c. enolase d. glycogen phosphorylase e. phosphofructokinase-2

51. Carbon 2 of lactic acid is the carbon that carries the hydroxyl group. In anaerobic glycolysis, carbon 2 of lactic acid comes from which carbon(s) of glucose? a. carbons 1 and 6 b. carbons 2 and 5 c. carbons 3 and 4 d. carbons 5 and 6 e. only carbon 1

52. Fructose can be metabolized via glycolysis without the regulatory restrictions of hexokinase and phosphofructokinase-1. Its uptake does not depend on insulin and fructose does not increase glycemia. Because of this, intravenous fructose administration to diabetics and other patients was once practiced but was promptly abandoned due to the development of life-threatening hypoglycemia and hypophosphatemia. These bad effects of fructose occur because one enzyme of fructose metabolism is more active than a second enzyme of fructose metabolism. Which answer below identifies these two enzymes? a. aldolase A (fructose-1,6-bisphosphate aldolase) is more active than hexokinase b. phosphofructokinase-1 is more active than fructose-1,6-bisphosphatase c. fructose-1-phosphate kinase is more active than glucose-6-phosphatase d. fructokinase is more active than aldolase B (fructose-1-phosphate aldolase) e. glucokinase is more active than aldolase B (fructose-1-phosphate aldolase)

54. Which of the following molecules can be a precursor for net gluconeogenesis during fasting? a. acetylcoenzyme A b. a free fatty acid c. ethanol d. lactate e. fructose

56. The biosynthesis of which of the following compounds from pyruvate requires both acetylCoA and ATP? a. lactate b. alanine c. oxalate d. citrate e. oxaloacetate

57. How many moles of high-energy nucleotide triphosphates (ATP + GTP) are needed in gluconeogenesis for the synthesis of 1 mole of glucose from 2 moles of pyruvate? a. 8 b. 6 c. 4 d. 2 e. 0 pyruvate carboxylase 1 ATP x2 PEPCK 1ATP x2 Phosphoglycero kinase

58. What is one consequence of fructose-1,6-bisphosphatase deficiency? a. failure of cells to metabolize glucose-6-phosphate via the glycolytic pathway b. accumulation of fructose phosphates in the liver c. inability to produce pyruvate from lactate d. hypoglycemia between meals e. pentosuria

59. Which of the following molecules is an intermediary metabolite in the gluconeogenesis pathway that is synthesized in the mitochondria but that cannot be directly transported into the cytosol? a. dihydroxyacetone phosphate b. phosphoenolpyruvate c. oxaloacetate d. aspartate e. malate

60. Ingestion of ethanol decreases the replenishment of muscle glycogen after exercise because of increased the formation of NADH. This increase in NADH formation inhibits gluconeogenesis from lactate because: a. the formation of NADH consumes the NADPH that is produced by the pentose phosphate shunt. b. NADH competes with phosphoenolpyruvate for phosphoenolpyruvate carboxykinase. c. the formation of NADH consumes the NAD+ that is needed to convert lactate into pyruvate. d. ethanol metabolism exhausts the intracellular stores of lactate. e. phosphoenolpyruvate carboxykinase is allosterically inhibited by NADH.

68. The ability of the liver to release glucose during starvation requires, among others, the activity of one of the following enzymes? a. glucokinase b. citrate synthase c. phosphofructokinase-1 d. fructose-l,6-bisphosphatase e. glycogen synthase

69. Which enzyme of the pentose phosphate pathway requires thiamine pyrophosphate (TPP) as a cofactor? a. glucose-6-phosphate dehydrogenase b. 6-phosphogluconate dehydrogenase c. phosphopentose isomerase d. transketolase e. transaldolase

70. The table below describes the effects of glucagon, insulin, glucose intake, overnight fasting and exercise on glycogenesis and glycogenolysis in muscle and in liver. Only one of these descriptions is correct. Answer this question by selecting the letter from the first column corresponding to the row that gives the correct description of the metabolic changes.

The next eight slides are about the integration of carbohydrate metabolism with lipid biosynthesis. These slides were removed from my lectures following Dr. Han’s plan. To avoid confusion and overlapping, all allusions to links between carbohydrates and lipid synthesis were removed from my lectures. However, not all topics related to the integration were taken care off. Therefore, I include some of the removed slides here.

In liver L-pyruvate kinase is one of the leading enzymes involved in lipid synthesis. In muscle the function of pyruvate kinase is to make ATP.

2) Nonoxidative steps of pentose phosphate shunt Misplaced slide? No, it is integration of glucose metabolism with lipid synthesis 2) Nonoxidative steps of pentose phosphate shunt Xylulose-5P the pentose that makes you FAT This slide shows a major cell signaling step from PPP to fatty acid synthesis. Xylulose-5P the pentose that makes you FAT

Phosphofructokinase-2 Fructose-2,6-bis-phosphatase Regulation of fructose-2,6-bis phosphate synthesis and break down HEXOSES Fructose-6-P Fructose-2,6-bis-phosphate ATP ADP Lipogenesis by activation of hepatic glycolysis PKA ATP Phosphofructokinase-2 PP2A Pi cAMP Bifunctional enzyme. Phosphorylated is phosphatase Dephosphorylated is kinase PKA is just that, protein kinase A Fructose-2,6-bis-phosphatase Fructose-2,6-P Fructose-6-P H2O Pi This slide is self explanatory if studied within the context of the complete lecture. xylulose-5-P comes from PPP when there is plenty of glucose PP2A is protein phosphatase 2A

Role of 2,6-Fructose-bisphosphate and phosphofructokinases-1 and -2 Phosphofructokinase-1 is the well-known glycolytic enzyme; phosphofructokinase-2 is exclusively a regulatory enzyme. PFK-2, when it is not phosphorylated, has kinase activity and catalyzes the phosphorylation of fructose-6-P in carbon 2, thus making fructose-2,6-P. When phosphorylated, phosphofructokinase-2 has phosphatase activity and dephosphorylates the carbon 2 of FDP-2,6 making fructose-6-P. The role of 2,6-FDP is to "convey" to the liver that there is plenty of hexoses and that glycolysis must be activated to support fatty acid synthesis. Simultaneously, insulin inhibits gluconeogenesis by lowering 3,5-cyclic-AMP.  In the liver, glycolysis is inhibited indirectly by cAMP which, inhibits liver pyruvate kinase and phosphofructokinase-1 by lowering 2,6-FDP and by activation of 1,6-FDP phosphatase. In the muscle, cAMP activates glycolysis, among others, by activation of glycogenolysis. This difference in regulation reflects the different roles of glycolysis in both organs. During stress or exercise, muscle requires energy, but the liver must regenerate glucose. In the muscle, phosphofructokinase-2 is a different enzyme than in the liver. In the muscle, the phosphorylation of phosphofructokinase-2 is on a different site than in the liver, and this phosphorylation activates glycolysis by a not well-understood mechanism. Insulin inhibits gluconeogenesis in liver through a complex signaling by decreasing cAMP, however, in diabetic patients the signal of insulin is weak and allows for gluconeogenesis. It is paradoxical that in diabetic patients gluconeogenesis can be activated even in the presence of hyperglycemia.

Abbreviated glycolysis, gluconeogenesis, and pentose shunt pathways and roles of Xu5P and Fru-2,6-P2 in lipogenesis Kabashima T et al. PNAS 2003;100:5107-5112 The roles of Xu5P in the activation of PP2A and PFK-2. The scheme illustrates the formation of Xu5P from fructose 6-phosphate (F6P) and glyceraldehyde 3-phosphate (GAP) by transketolase, which activates PP2A. PP2A activates 6-phosphofructokinase-2 which increases Fru-2,6-P resulting in activation of PFK-1. The same PP2A also activates ChREBP in the nucleus increasing the expression of enzymes involved in lipid synthesis, including liver pyruvate kinase, citrate lyase (ACL), acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS).

Can fat make you slim? The old dogma that all calories are equally responsible for gaining weight is not entirely true. Polyunsaturated fatty acids (PUFA) negatively regulate lipid synthesis and could decrease the epidemics of obesity and metabolic syndrome. No all factors that mediate the obesity epidemics are well understood. d