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14 Cards in this Set

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1) What are the 4 unique reactions that allow gluconeogenesis to proceed from glycolysis?

How much energy and reductive power are needed for synthesis of glucose from pyruate ?
1) PC (pyruvate carboxylase), PEPCK (phosphoenol-pyruvat carboxykinase), FBPase 1 (fructose 1,6-bisphosphatase) and Glc-6-Ptase (glucose-6-P phosphatase).

2NADH and 4ATP +2GTP.
2) What may be two functions for transport of malate from the mitochondria to the cytosol for gluconeogenesis?

How is P-enolpyruvate transported from the mitochondria to the cytosol (discussed in lecture)?
2) If the PEPCK is present in the cytosol in the liver cell as in the mouse or rat, then the oxaloacetate must be converted to malate via malate dehydrogenase, (MDH) because OAA cannot permeate the mitochondrial membrane. The formed malate is transported into the cytosol to be reconverted back to OAA (via MDH) and then to PEP via PEPCK. This process also brings to the cytosol reducing power (NADH) via the cytosol MDH.

PEP is transported via specific membrane protein transporter and this occurs in the pigeon & rabbit liver because PEPCK is exclusively located in the mitochondria.
3) How is Protein kinase A involved in regulating liver glycolysis and gluconeogenesis?

What enzymes and what metabolites are affected?
3) PKA phosphorylates liver pyruvate kinase and makes it inactive, have less affinity for the substrate PEP and higher affinity for the inhibitors alanine and ATP. It also phosphorylates liver PFKII/FBPase II causing them to be less active as a PFKII and more active as a FBPaseII.

This lowers the Fru-2,6-bisP concentrations in the cell and therefore glycolysis is no longer activated and gluconeogenesis is no longer inhibited. Thus gluconeogenesis flux predominates.
4) What are the allosteric effectors of P-fructokinase-1 and Fru-1,6-bis Pase-1? Explain their physiological significance? What are the allosteric effectors of liver pyruvate kinase and explain their physiological significance?
4) PFKI: AMP & Fru2,6-bisP, activators. ATP and citrate are inhibitors. High [AMP] is an indicator of low energy state, thus glycolysis is needed. High [ATP] is an indicatior of a high energy state thus no or low glycolysis activity is needed. High [Citrate] is an indicator of high TCA cycle activity. Thus there is no need for active glycolysis to make ATP. Liver [Fru-2,6 bis-P] is high when there is excess blood [glucose] and thus liver glycolysis is stimulated.
FBPase I: AMP and fru-2,6-bis-P are inhibitors. Since they are activators of glycolysis they are appropriate inhibitors of gluconeogenesis to prevent a futile cycle.
Pyruvate kinase (PK): Fru-1,6-bis-P, an activator and alanine and ATP, inhibitors. High
[ Fru-1,6 bis-P] indicates active glycolysis and thus you want an active PK. High [ATP} means glycolysis not required and thus glycolytic activity is inhibited and pyruvate kinase activity is no longer required. [Alanine] is increased in gluconeogenesis due to increased proteolysis and thus is part of the mechanism to decrease PK and glycolytic activity particularly when PC and PEPCK activities are increased.
5) Describe the covalent modification and allosteric regulation of phosphofructokinase 2 /fructobisphosphatase 2 (PFKII/FBPaseII), the enzyme that forms and degrades fructose-2,6-bis-P.
5) PKA, Protein kinase A phosphorylates liver PFKII/FBPase II causing it be less active as a PFKII and more active as a FBPaseII. This lowers the Fru-2,6-bisP concentrations in the cell and therefore glycolysis is no longer activated and gluconeogenesis is no longer inhibited. The PFKII/FBPase II activities are catalyzed by one protein which has the PFKII activity at the N terminal and FBPase II activitity at the C-terminal. The covalent modification occurs on a Ser residue at the N-terminal. This inactivates the PFK II activity and stimulates the FBPase II activity.
6) Show how the hormone, glucagon, regulates fru-2,6-bis-P levels in liver?
6) Glucagon binds to the glucagon receptor in the liver plasma membrane which then is able to bind to the alpha subunit of the G protein complex of abg subunits The Galpha subunit, which has bound to it a GDP, exchanges it with GTP. The beta, gamma subunits then dissociate from the complex to yield a Galpha subunit-Receptor-glucagon-GTP-complex. The GTP- Galpha subunit is then released and then binds to the inactive adenylate cyclase activating it and cAMP is synthesized. Then protein Kinase A is activated by cAMP. PKA then phosphorylates the liver PFKII/FBPaseII and converts it essentially to a FBPaseII as stated in answer 5 above and thus the [Fru-2,6-bis-p] is lowered. The GTP- G alpha complex also has GTPase activity and when the GTP is hydrolyzed, the complex can no longer stimulate the adenylate cyclase. When glucagon concentration falls or insulin becomes the predominant hormone the production of the GTP- Galpha subunit stops because the glucagon no longer binds to the receptor. The G-alpha subunit after hydrolysis of the GTP to GDP then reforms the G protein complex with the Gbeta, gamma subunits. The [cAMP] is decreased due to cAMP phosphodiesterase activity. The PKA is no longer active as the R subunits bind to the C subunits. Protein phosphatase takes over and dephosphorylates the PFKII/FBPase II enzyme complex and essentially converts it back to PFKII activity and thus the [Fru-2,6-bis-P] is increased.
7) Discuss the regulation of hexokinase. Contrast the properties and physiologic roles of hexokinase and glucokinase.
7) hexokinase has a low Km for glucose but is allosterically inhibited by glucose-6-P. Thus when there is excess glucose in the blood there is inhibition of the hexokinase step when there is excess glucose 6-P which is then redirected towards glycogen synthesis. The hexokinase is important for muscle cells but not liver cells. Hexokinase activity is very low in liver. When there is high glucose in the blood there is an induction in liver of glucokinase activity. This enzyme has a high Km for glucose equal to about the normal glucose concentration in the blood but the enzyme is not inhibited by glucose-6-P.
8) Describe the regulation of liver pyruvate kinase.
8). See answers 3 and 4 concerning pyruvate kinase. Allosteric regulation and covalent regulation play important roles.
9) Predict the major consequence of each of the following enzymatic deficiencies:
a) Glc-6-Ptase in liver.
b) PFKinase II in liver.
c) PFKinase II in heart muscle.
9. a) Glc-6-Ptase deficiency would not allow liver to provide the blood and other tissues with glucose. Thus lack of the Glc-6-Ptase causes accumulation of Glc-6-P in liver which is eventually converted to glycogen. This is Von Gierke’s disease whose patients also have low blood glucose.
b &c) Same answer. Reduced or no synthesis of Fru-2,6-bis P, the important allosteric activator of PFK-I. Therefore glycolysis in those tissues will be lower than normal. In liver you will have a higher rate of gluconeogenesis because the FBPase-I will not be inhibited.
10) What are the key enzymatic differences between liver, muscle and brain that account for their different utilization of metabolic fuels?
10) Liver has Glc-6-Ptase, Pyruvate carboxylase and PEP carboxykinase. Muscle and brain do not have these enzymes. Thus liver can synthesize glucose from non-carbohydrates and release glucose to the blood. Muscle and brain are mainly if not completely dependent on the blood glucose.
11) Describe the formation of cyclic AMP as stimulated by either glucagon or epinephrine. In your description please indicate the roles of the hormone receptor, the G proteins, and adenylate cyclase. Where do all these interactions occur?
11) Glucagon or epinephrine binds to its receptor which then reacts with the G protein complex, Galpha,beta,gamma.This causes an exchange of GDP attached to the Galpha subunit with GTP.This complex dissociates from the hormone-receptor to yield a Galpha complex with GTP bound to it.. The Galpha-GTP complex then interacts with adenylate cyclase and activates it to catalyze formation of cAMP. If the hormone levels decrease then the hormone-receptor-Galpha-GTP complex dissociates from the adenylate cyclase making it inactive. The GTPase activity of Galpha then predominates and hydrolyzes the GTP to GDP. The Galpha-GDP then recombines with the Gbeta,gamma peptides to reform the Galpha,beta,gamma complex. This answer is similar to answer for question 6.
12) What is the mechanism of activation of the cyclic AMP dependent protein kinase by cAMP?
12) 4 cAMP + R2C2 (inactive) <-----> 2C (active) + R2(cAMP)4. cAMP bind to the regulatory (inhibitory) subunits, R, releasing the catalytic subunits, C which are now active.
13) Indicate by one word, “Stimulates” or “inhibits”, the action of insulin on the following processes.
a) gluconeogenesis in liver___________
b) entry of Glc in muscle & adipose cells____
c) Glycolysis in liver_____________
d) Glycogen synthesis in liver & muscle____
a)Inhibits
b) Stimulates
c) Stimulates
d) Stimulates
14) Match each metabolic pathway in the left column with its major role in metabolism from the right column.

a) Glycolysis _____
b) Gluconeo-glucose
genesis _________
c) Pentose-P Formation
pathway_________
d) Glycogen synthesis _____ -P synthesis

1) control of blood
2) NADH & FADH2
3) Storage of Fuel
4) NADPH & Ribose-5
5) Production of ATP during short sprints.
A) 5. Production of ATP during short sprints.

B)1. control of blood

C)4. NADPH & Ribose-5

D)3. Storage of Fuel