Chapter 16: Glycolysis & Gluconeogenesis

GLUT4 (5mM)

-in Muscles and fat cells - amount in muscle plasma increases with endurance training

Insulin

-levels rise AFTER each meal in response to increasing blood glucose levels -promotes glycolysis and inhibits gluconeogensis

Glucagon

-levels rise during fasting and glucose is scarce -promotes gluconeogensis and inhibits glycolysis

GLUT1 and GLUT3 (1mM)

-located in all mammalian tissues -basal glucose uptake

GLUT5

-located in small intestine -primarily a fructose transporter

1. ADP (adenosine diphosphate) 2. If ATP required (after a meal) 3. If glucose is required (before a meal/ fasting

1. What inhibits Phosphoenolpyruvate carboxykinase 2. When does glycolysis predominate? 3. When is gluconeogenesis favored?

1. Fructose 1,6-biphosphatase (FBPase) 2. Metabolically irreversible 3. The flux through the gluconeogenesis pathway

1. Which enzyme bypasses the Phosphofructokinase reaction? 2. What type of reaction is it? 3. It's a allosteric enzyme that controls what?

50%, 100%

1mM=_______ saturated, 2mM=_______ saturated

1. Pyruvate carboxylase 2. Fructose 1,6 biphosphate 3.phosphoenol-pyruvate carboxykinase 4. Glucose 6-phosphotase

4 enzymes specific to gluconeogensis not in glycolysis

PFK2 and FBPase2

A bifunctional enzyme contains an N-terminal regulatory domain followed by kinase and phasphatase domains

Liver .... liver deals with blood levels muscle does not!

All ow blood glucose levels, the glucagon-triggered cyclic AMP cascade lead to phosphorylation and inactivation of pyruvate kinase. Does this happen in the liver or muscle?

During gluconeogenesis, where is the newly formed glucose used?

By brain and contracting muscle

-Hypoxia -lactic acidosis fermentation

Cancer cells grow faster than blood vessels and are unable to obtain oxygen efficiently aka (___________) -________ ____________ ______________ is the primary source of ATP

a. Lactate 2ATP b. Acetyl coA 30 ATP

Complete flow of the Warburg Effect Glucose —

NO there is a lot of ATP when muscle is at rest

DO you need to turn on glycolysis when muscle is at rest?

Lactic acidosis: accumulation of lactic acidic in blood Hypoglycemi: low blood glucose level

Define lactic acidosis and hypoglycemia

A. No insulin-GLUT4 inside cell-decreased glucose uptake B. Insulin-GLUT4 in the plasma membrane-increase glucose uptake

Describe what is occurring in images (A) and (B)

No!

Does muscle have glucose 6-phosphatase?

Hypoxia-induced transcription factor (HIF-1)

During hypoxia, what increases the expression of glycolytic enzymes and glucose transporters GLUT1 & GLUT3?

Glucokinase, which is not inhibited by glucose 6-phosphate

For Hexokinase regulation in the liver, what is the special hexokinase the liver has?

50-fold lower

Glucokinase phosphorylated glucose only when it is abundant and has a ___________________________ affinity for glucose than kexokinase (Km=5mM vs 0.1mM)

False

Gluconeogenesis is a reversal of glycolysis

fasting and starvation

Gluconeogenesis supplies almost all of body's glucose and maintains normal glucose levels during ....

Glycogen synthesis and pentose phosphate pathway

Glucose 6-phosphate is used in ________ ________ and in the ________ ___________ _______

Muscle

Glycolysis in __________ is regulated to meet the need for ATP

Hyperbolic, sigmoidal

High concentrations of ATP convert the _________ binding curve of fructose 6-phosphate into a ___________ one

By altering fructose 2,6-biphosphate level

How does blood glucose levels regulate glycolysis and gluconeogenesis

Glycerol (from hydrolysis of triacylglycerols) is converted into dihydroxyacetone phosphate -enters as glyceraldehyde 3-phosphate

How does glycerol enter gluconeogenesis? What does it enter as?

1. Skeletal has ATP production for contraction and the energy status is important 2. Liver regulates blood glucose levels and glucose levels are important (during fasting to maintain blood glucose level)

How is glycolysis controlled in skeletal muscle vs. liver?

GLUT4

Insulin promotes glucose uptake into muscle cane fat. _______ is the insulin-responsive glucose transporter ....after a meal, this transporter is active

NO because the liver does not produce lactate

Is low pH a regulator of Phosphofructokinase in liver? Why?

Phosphoenolpyruvate (PEP)

Oxaloacetate is simultaneously decarboxylated and phosphorylated to ______________________ in the cytosol by PEP carboxykinase

Malate

Oxaloacetate is transported to the cytosol as ___________

reciprocally, phosphorylation

PFK2 and FBPase2 are controlled ___________ by ____________ of a single serine residue

1. ATP (even energy charge is high) 2. Alanine (when building blocks are abundant) Fructose 1,6 -biphosphate activates the pyruvate kinase ?= pyruvate kinase

Pyruvate kinase is allosterically inhibit by high levels of ....

Noncarbohydrates Precursors

Synthesis of Glucose (Gluconeogenesis) is from ...?

FALSE : only one pathway is activated at a time

T/F Gluconeogensis and glycolysis are coordinated at the same time

Fructose 1,6-biohosphate ATP and alanine

The L-type and M-type isoforms are activated by ____________ and inhibited by ______ and __________

1. AMP 2. Increases 3. Ratio is lowered 4. Inhibited

The allosteric inhibition by ATP is reversed by_____(1)___ The activity of the enzyme _____(2)_____ when the ATP/AMP________(3)_______ When pH drops, the enzyme is _______(4)________

High levels of ATP (high energy charge) and citrate (biosynthetic intermediates are abundant)

What (2 things) inhibit phosphofructokinase and turn off glycolysis

1. Hexokinase 2. PFK 3. Pyruvate Kinase

What 3 enzymes are inhibited when ATP is high?

Glucose 6- phosphate (product inhibition)

What allosterically inhibits Hexokinase?

High levels of ATP and citrate

What allosterically inhibits Phosphofructokinase in the liver?

The three irreversible reactions o glycolysis

What are bypassed in gluconeogenesis by new steps?

Generate ATP and provide carbon skeletons for biosynthetic pathways

What are the 2 functions of Glycolysis?

Hexokinase Phosphofructokinase-1 Pyruvate kinase

What are the 3 irreversible steps in glycolysis catalyzed by?

1. Reversible allosteric control- milliseconds 2. Regulation by reversible phosphorylation-seconds 3. Transcriptional control -hours (long term regulation)

What are the 3 mechanisms that control enzymes and make glycolysis pathways tightly controlled?

Lactate, amino acids and glycerol

What are the main precursors for gluconeogenesis?

Lactate and other precursors

What determines the rate of gluconeogenesis?

Glucose concentration

What determines the rate of glycolysis?

Lactic acidosis and Hypoglycemia

What does deficiency in gluconeogenic enzymes cause?

1. Stimulates Phosphofructokinase 2. Inhibits Fructose 1,6-bisphosphatase

What does fructose 2,6-biphosphate stimulate and inhibit?

ATP binds to a regulatory site within the PFK and INHIBITS PFK by reducing its affinity for its substrate fructose -6P

What does high concentrations of ATP cause?

Activates FBPase2 and inhibits PFK2

What does phosphorylation do which lowers the level of F-2, 6-BP, thereby turning off glycolysis. Gluconeogenesis predominates

a family of transporters

What enables glucose to enter and leave animal cells?

Glucagon levels rise in the blood and trigger a cyclic AMP cascade, leading to phosphorylation by PKA —

What happens when glucose is scarce?

Rates of glucose uptake and glycolysis

What have tumors increased?

Inhibited by ADP Activated by acetyl CoA

What inhibits Pyruvate carboxylase and what activates it?

-rapidly growing tumors obtain ATP by converting glucose to lactate even in the presence of oxygen -tumors easily visualized by tomography using a non-metabolizable glucose analog

What is Aerobic Glycolysis (Warburg Effect)?

Fructose 2,6-bisphosphate (F-2,6-BP)

What is a potent allosteric activator of phosphofructokinase in the liver?

Aerobic Glycolysis or Warburg Effect

What is a property of rapidly growing cells?

Phosphofructokinase

What is the first irreversible reaction unique to the glycolytic pathway that also catalyzes the committed step?

Maintain blood-glucose

What is the main function of the liver?

Phosphofructokinase (PFK)

What is the major control element of glycolysis?

2-18FD-deoxyglucose

What is used in to help visualize tumors in a PET and CAT scan?

The inhibition of phosphofructokinase

What leads to the inhibition of hexokinase?

Enzyme becomes dephosphorylated, which activates PFK2 and inhibits FBPase2 increasing f-2, 6 BP level; and glycolysis is stimulated —

What occurs when glucose is abundant?

L-type M type

What predominates in the liver and what predominates in the muscle and brain?

Reversible phosphorylation

What regulates the L form in pyruvate kinase regulation in the liver?

AMP (low pH inhibits PFK activity by augmenting the inhibitory effect of ATP.... contracting muscle produces lactate which lowers pH and to avoid damage, PFK is inhibited when pH drops due to lactate accumulation)

What reverses the inhibition of PFK by ATP?

High levels of AMP (low energy)

What stimulates phosphpfructokinase (Glycolysis turned on) but inhibit fructose 1,6-biphosphatase (gluconeogenesis turned off)

Mitochondrial

What type of enzyme is pyruvate carboxylase?

Carboxylation of pyruvate to oxaloacetate

What's the first step in gluconeogenesis?

5mM 11mM

What's the normal blood glucose level? After a meal?

When blood glucose levels are low

When does fructose 2,6-biphosphate (F2, 6-BP) convert to fructose 6-phosphate?

At high blood glucose levels

When does fructose 2,6-biphosphate levels increase?

When glucose is abundant

When is glycolysis accelerated in the liver?

1. Fructose 6-phosphate 2. Glucose 6-phosphate

When phosphofructokinase is inactive, ___1____ levels rise and it is converted to ____________2____________

The brain and muscle

Where does glucose go first when glucose supply is limited?

In the cytoplasm

Where does glycolysis take place?

In the liver only

Where is free glucose essentially generated?

Cytoplasm

Where is oxaloacetate shuttled into and converted into Phophoenolpyruvate?

Liver and kidney

Where is the major site of gluconeogenesis? And another site where some gluconeogenesis occurs?

Glucose 6- phophatase

Which enzyme converts glucose 6-P to free glucose and is present only in liver and kidney? And is hydrolyzed to glucose in the lumen of the ER by membrane-bound glucose 6-phosphate

-Pyruvate carboxylase and phophoenolpyruvate carboxykinase

Which enzymes bypass the pyruvate kinase reaction of glycolysis?

GLUT1- GLUT5

Which glucose transporters consist of about 500 amino acids and have 12 transmembrane domains?

ATP and alanine

Which glycolytic enzymes inhibit pyruvate kinase?

GLUT4

Which transporter has a Km of 5mM and mediates the entry of glucose into muscle and fat cells?

GLUT2

Which transporter is present in liver and pancreatic beta-cells and has very high Km for glucose (15-20mM)?

GLUT5

Which transporter is present in the small intestine and functions as a fructose transporter?

GLUT1 and GLUT3

Which transporters are present in nearly all mammalian cells and are responsible for basal glucose uptake (Km=1mM)

GLUT1 and GLUT3

Which transporters transport glucose into cells at normal blood glucose levels?

6 nucleotide triphosphate

____ _______ _______moelcules are required for synthesis of glucose from pyruvate, while only 2 molecules of ATP are generated in glycolysis

Citrate

_________ is an activator of fructose 1,6-biphosphate season and promotes gluconeogenesis

GLUT2 (15-20mM)

located in liver and pancreatic beta cells -in pancreas, plays role in reg. Of insulin -in liver, removes excess glucose from blood