Cellular Respiration Biochemistry: Triose Phosphate Isomerase, Glycolysis, Gluconeogenesis, Exams of Biochemistry

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Examination III Key

MCMP 208 – Biochemistry for Pharmaceutical Sciences I

April 4, 2017

Correct answers in multiple choice questions are indicated in RED and underlined.

Correct answers to essay questions are indicated in RED in comic book font.

In some cases and explanation is provided in BLUE/BLUE

MULTIPLE CHOICE. For problems 1 to 17 , select from the list immediately following each question the single most correct choice to complete the statement, solve the problem, or answer the question. Mark that answer on your answer sheet. [3 points each]

1. The mechanism used in the reaction catalyzed by triose phosphate isomerase involves

 a bis-phosphorylated intermediate  removal of a molecule of water in a lyase class reaction  phosphorylation involving a molecule of ATP  hydrolysis of a phosphate ester  hydrolysis of a glycosidic bond  an ene-diol intermediate  formation of a Schiff base with the side chain of a lysyl residue in the enzyme  generation of NADH + H+

2. Under anaerobic conditions or in the absence of functional mitochondria (such as erythrocytes), glycolysis in mammalian cells generates what product(s) that contain the carbons from glucose?

 ethanol and carbon dioxide  carbon dioxide only  pyruvate only  pyruvate and lactate  pyruvate and carbon dioxide  acetyl-coA and carbon dioxide  lactate only  lactate and carbon dioxide  lactate and ethanol and carbon dioxide  lactate and acetyl-coA and carbon dioxide

Acetyl-CoA and carbon dioxide require oxygen and mitochondria and cannot be produced by erythrocytes or in anaerobic (anoxic) conditions. Production of ethanol does not occur in mammals. Production of pyruvate happens but this is not sustainable due to eventual depletions of NAD+^ so in these conditions (or in erythrocytes) the pyruvate must be converted to lactate.

3. While most human cells carry out gluconeogenesis, what is different about gluconeogenesis in liver cells compared to gluconeogenesis in cells of other tissues and organs?

 Only liver cells can utilize amino acids for gluconeogenesis. Not true, all cells can.  Only the liver can produce glucose from fatty acids. Not true, no cells can do this.  Glucose can be made from fatty acids in most cells but not in liver cells. Not true, no cells can do this.  Liver cells are the only cells that can produce fatty acids from glucose. Not true, all cells can.  Liver cells are the only cells that can produce D-glucose via gluconeogenesis. This is because liver cells are the only cells that express significant levels of Glucose-6-phosphatase.  Liver cells are the only cells that can produce ribose-5-phosphate via gluconeogenesis. Not true, no cells can do this without involving the PPP.

4. There is one intermediate in gluconeogenesis that is not an intermediate in glycolysis. The gluconeogenic enzyme that makes this intermediate (that is not found in glycolysis) is

 lactate dehydrogenase  6-phosphogluconate dehydrogenase  phosphoglucose mutase  PEP-carboxykinase  pyruvate kinase  pyruvate carboxylase The unique metabolite is oxaloacetic acid, which is made in gluconeogenesis by carboxylating pyruvate.  malate dehyrogenase  pyruvate dehydrogenase

5. The pentose phosphate pathway uniquely produces what useful products and in what ratio?

 nine glucose to one glucose-6-phosphate  two NADPH to one fructose-6-phosphate  two NADPH to two fructose-6-phosphate  two NADPH to two fructose-6-phosphate and one 3-phosphoglyceraldehyde Products but not unique  two NADPH to one ribose-5-phosphate  two NADPH to one ribulose-5-phosphate  nine glucose-1-phosphate to one glucose-6-phosphate  nine glucose-1 phosphate to one glucose  one ribose-5-phosphate to two xylulose-5-phosphate Unique PPP products but not useful

6. Which pathway (or combination of pathways that are operating at the same time) is/are capable of converting a molecule of glucose to 6 molecules of carbon dioxide?

 gluconeogenesis  glycolysis  glycolysis and gluconeogenesis  pentose phosphate pathway  pentose phosphate pathway with gluconeogenesis  pentose phosphate pathway with glycolysis

7. A key intermediate in the breakdown of fructose obtained from the diet is

 fructose-1,6-bisphosphate  fructose-6-phosphate  fructose-2,6-bisphosphate  fructose-1-phosphate  UDP-fructose  the lactone that is produced after oxidation of the anomeric carbon of fructose-6-phosphate  glucose-1-phosphate  UDP-glucose

Of the above, only F1P is a metabolite of fructose metabolism that is not also a later metabolite found in other pathways, some of which are unrelated to metabolism of dietary fructose (i.e., UDP-glucose, G1P, and F2,6bisP). Choice 6 is fictitious and does not occur in carbohydrate metabolism.

8. The physiologic significance of glycogen is that it is most useful for

 reducing blood glucose during periods of elevated blood glucose  being the only way to store energy-rich molecules that cells can metabolize to make ATP  providing glucose molecules when the need for glucose is greater than can be met by the other pathways (not involving glycogen) that can make glucose available to the cell  being the only phosphate-free storage form of energy-rich molecules that cells can use to make ATP  being the only way to keep glucose inside of cells  being the only source of molecules that can serve to fill-up the citric acid cycle via anaplerotic reactions

Generally, triglycerides also are phosphate-free energy-rich molecules that can be stored to make ATP at other times. There are other ways to fill up the citric acid cycle (amino acid metabolism) and there are other ways to keep glucose inside cells (phosphorylate it). Choice 1 is incorrect because glycogen synthesis during periods of elevated glucose levels is a useful aspect of glycogen, it is not the MOST useful use of glycogen, as evidenced from glycogen storage diseases where people have hereditary deficiency of enzymes that break down glycogen. In these cases there can be muscle weakness and severe fasting hypoglycemia.

9. Given a pair of molecules (or atoms) capable of being oxidized and reduced, the electrons will generally leave the one with the

 greater reduction potential  lower reduction potential  greater concentration  lower concentration  greater entropy  lower entropy  greater charge  lower charge  greater polarity  lower polarity

10. Functionally, flavin coenzymes differ from nicotinamide coenzyme in that flavin coenzymes

 always participate only in 2 electron reactions  never participate in 2 electron reactions  always function as a prosthetic group  never function as a prosthetic group  always contain an AMP as a part of their structure  never contain an AMP as part of their structure

11. One molecule of acetyl-coenzyme A yields what energy-rich molecules when metabolized via the citric acid cycle?

 1 NADH + 1 GTP  2 NADH + 1 GTP  3 NADH + 1 GTP  4 NADH + 1 GTP  5 NADH + 1 GTP  1 FADH 2 + 1 GTP  2 NADH + 1 FADH 2 + 1 GTP  3 NADH + 1 FADH 2 + 1 GTP  4 NADH + 1 FADH 2 + 1 GTP  2 NADH + 2 FADH 2 + 1 GTP

12. Reactive oxygen species form extensively in the mitochondria because

 oxygen is only found in the mitochondria  electrons are only found in the mitochondria  electrons are only moved from one molecule to another in the mitochondria  oxygen reacts with elements of the electron transport system to pick up one electron  iron is very high in the mitochondria  the mitochondria have an extensive system of membranes providing many places for reaction with reactive oxygen species

13. Which coenzyme is NOT involved in the reaction catalyzed by pyruvate dehydrogenase?

 coenzyme A  coenzyme Q  NAD+  FAD  lipoamide  thiamine pyrophosphate

14. In addition to its role as a solvent, water has a very special and important role in the mitochondrial electron transport because water is

 the final recipient of the oxygens from acetyl Co-A in the citric acid cycle  a key intermediate in the synthesis of ATP  the final molecule to hold the electrons from the acetyl-CoA in the citric acid cycle

 the source for molecular oxygen that is generated by electron transport  the source of the electrons that are transported in the electron transport system  the molecule that is pumped out of the mitochondria as the energy intermediate resulting from electron transport

15. Aside from the function of the mitochondrial ATP synthase to make ATP, this enzyme also

 transports ADP and ATP across the inner mitochondrial membrane  transports inorganic phosphate across the inner mitochondrial membrane  transports water across the inner mitochondrial membrane  transports protons across the inner mitochondrial membrane  transports electrons  reduces molecular oxygen while transporting water across the inner mitochondrial membrane  shuttles reducing equivalents from the cytosol across the inner mitochondrial membrane

16. Treatment of liver cells with 2,4-dinitrophenol will cause what to happen?

 increased gluconeogenesis  increased pentose phosphate pathway activity  increased mitochondrial electron transport and/or decreased ATP levels  increased glycogen synthesis  decreased mitochondrial electron transport  increased ATP synthesis by oxidative phosphorylation

DNP is an uncoupler that collapses the proton gradient across the inner mitochondrial membrane. This will slow ATP synthesis and lower ATP levels as well as allow ETS (and proton pumping) to speed up as it eliminates respiratory control of the ETS. Gluconeogenesis, the PPP, and glycogen synthesis are anabolic pathways which tend to get shut down when ATP levels fall.

17. Under physiological conditions inside cells the most reactive (i.e., shortest-lived) of the reactive oxygen species is

 singlet oxygen  triplet oxygen  ozone  superoxide  hydrogen peroxide  hydroxyl radical

ESSAY PROBLEMS. Write your answers to problems 18 to 22 in the space immediately below each problem.

18. [5 points] There are three glycolytic intermediates that also are either directly used or directly made by the pentose phosphate pathway. Pick ONE of these and provide (a) its structure; (b) its name; (c) the name of the enzyme (or two enzymes) that makes it in glycolysis; (d) the name of the enzyme (or two enzymes) that makes it in gluconeogenesis; and (e) the name of the enzyme (or two enzymes) in the pentose phosphate pathway that uses it or makes it (as a final product of the pathway, not an intermediate in the PPP). Label the enzyme names in your answer with Glycolysis, Gluconeogensis, or PPP.

The three possible choices for correct answers are glucose-6-phosphate, fructose-6- phosphate, and 3-phosphoglyceraldehyde. Each possible answer is shown below (only one is needed for full credit).

Glucose-6-phosphate Used in PPP by Glucose-6-phosphate dehydrogrenase Made in glycolysis by hexokinase (and glucokinase which is an form of hexokinase) Made in gluconeogenesis by phosphoglucose isomerase

Fructose-6-phosphate Made in PPP by transketolase and transaldolase Made in glycolysis by phosphoglucose isomerase Made in gluconeogenesis by fructose-1,6-bisphosphatase

3-phosphoglyceraldehyde Made in PPP by transketolase Made in glycolysis by aldolase and triose phosphate isomerase Made in gluconeogenesis by 3-phosphoglyceraldehyde dehydrogenase

19. [6 points] Describe the multistep process (including the names of the key elements) by which epinephrine stimulates glycolysis in muscle. You may use a diagram, though this is optional.

 Epinephrine leads to activation of PKA. [This occurs via several signaling steps that were not covered in detail in lecture and which are not required for full credit.]  Active PKA phosphorylates the muscle form of the bifunctional enzyme. This activates its PFK-2 activity and inhibits its F2,6-bisPase activity, leading to increased Fructose-2,6-bisphosphate.

 Increased F2,6-bisP allosterically activates phosphofructokinase-1 (PFK-1, or just PFK), which increases glycolysis. [F2,6-bisP also allosterically inhibits F1,6bisPase, which results in decreasing glycolysis, but this is not required for full credit.]

20. [6 points] Even though glycogen contains no phosphate, the two products of glycogenolysis are mostly glucose-1-phosphate along with a minority of glucose molecules. A. [3 points] Explain how glucose-1-phosphate is produced and why it is not the only product of glycogenolysis.

G1P is produced from glycogen by phosphorolysis of a terminal glucose linked via a α1- glycosyl bond by glycogen phosphorylase. Nearly all of the linkages in glycogen are α1-4, so nearly all of glucoses are released as glucose-1-phosphate.

B. [3 points] Explain why glucose is produced by glycogenolysis and why glucose is the minority product of glycogenolysis.

Glucose is produced from glycogen by hydrolysis of a terminal glucose linked via a α1- glycosyl bond by glycogen debranching enzyme. Only a small fraction of the linkages in glycogen are α1-6, so only a small fraction of glucoses are released as glucose.

21. [6 points] Of the enzymes in the cyclic part of the citric acid cycle, citrate synthase, succinyl-CoA synthetase, and succinate dehydrogenase are similar to reactions that are found in lipid metabolism. The remaining reactions each have strong similarity to at least one other enzyme seen in carbohydrate metabolism. Pick three enzymes in the cyclic part of the citric acid cycle (excluding the three listed here that resemble lipid metabolism) that catalyze different kinds of reactions. For EACH of the three you pick (which must meet these criteria), give the name of the enzyme in the citric acid cycle and the name of ONE different enzyme (involved in any aspect of carbohydrate metabolism) that catalyzes a similar type of reaction (using a different substrate, of course.) Make sure that in your answer you clearly indicate the pairings and for each pair which one in the citric acid cycle enzyme and which is the “other” enzyme.

Of the 5 remaining enzymes, two (malate dehydrogenase and isocitrate dehydrogenase) are oxidoreductases that oxidize secondary alcohols to ketones, 2 (aconitase and fumarase) are water removing lyases, and one carries out oxidative decarboxylation of an alpha keto acid. Since the answer requires three different reaction types, all three are required for full credit. Thus the answer is as follows:

CA cycle enzyme: Either fumarase or aconitase; other enzyme: either enolase or aconitase or fumarase (not the same one as indicated for the CA cycle enzyme)

CA cycle enzyme: Either malate dehydrogenase or isocitrate dehydrogenase; other enzyme (any one of): 6-phosphogluconate DH, lactate DH, or either of isocitrate DH or malate DH (no the same one as indicated for the CA cycle enzyme)

CA cycle enzyme: α-ketoglutarate dehydrogenase; other enzyme: pyruvate dehydrogenase

22. [6 points total] In mitochondrial electron transport, there are 4 enzymes or enzyme complexes that funnel electrons to coenzyme Q (ubiquinone) from molecular sources other than reduced coenzyme Q. One of these is directly involved in lipid metabolism. A. [3 points] What are the names of the three enzymes or enzyme complexes that are not directly involved in lipid metabolism?

Complex I, complex II (or succinate dehydrogenase), and 3-phosphoglycerol dehydrogenase.

B. [2 points] All 4 of these enzymes and enzyme complexes have a common location and one structural feature that is functionally significant (but is unrelated to the proteins’ location). What is this common structural feature that is functionally significant among these 4 enzymes?

All contain a flavin coenzyme (either FAD or FMN) as a prosthetic group.

C. [1 point] Of these 4 enzymes and enzyme complexes, which one is distinct from the other three in its role in generating the intermediate energy form that is used to drive mitochondrial ATP synthesis?

Complex I is distinct from the other three in that it pumps protons out of the mitochondrial matrix as it transports electrons. The other three do not pump protons.

Note that this question had a small typo in it originally (it is corrected above) that did not change the meaning of the question. It originally asked about “of the 4, the one that is distinct from the other 2”. It also could have been corrected to ask “of the 3, the one that is distinct from the other 2” with the same answer being correct (except “other three” should be changed to “other two” in each instance.)