CFB 8: Glucose Metabolism

What is the major dietary carbohydrate?

Glucose

What percent of daily glucose intake is used by the brain?

75%

How is glucose metabolized?

Glycolysis

Is glycolysis universal?

Yes

How are other carbohydrates (fructose, galactose, mannose) metabolized?

Conversion to glycolytic intermediates

Glycolysis is the conversion of glucose to what in aerobic conditions?

Pyruvate

Glycolysis is the conversion of glucose to what in anaerobic conditions?

Lactate

If glucose enters cells by facilitated diffusion, it will leave the same way, so how do you keep it there?

Phosphorylation

What enzyme catalyzes:

Glucose + ATP → Glucose-6-Phosphate + ADP

Hexokinase/glucokinase

What enzymes phosphorylate glucose?

hHexokinase and glucokinase

What term describes the set of enzymes that have different amino acid sequences but catalyze the same reaction?

Isoenzymes (Isozymes)

What is the difference between what hexokinase and glucokinase can phosphorylate?

Hexokinase: can phosphorylate other hexoses

Glucokinase: specific for glucose

Where does hexokinase vs. glucokinase work?

Hexokinase: ubiquitous

Glucokinase: restricted to liver and pancreatic β cells

Is hexokinase or glucokinase inhibited by G6P?

Hexokinases

Hexokinase is always active unless...

Unless G6P has accumulated

What helps clear glucose from the blood?

Liver glucokinase

What inhibits hexokinase?

G6P

What does glucokinase do to blood glucose in the liver?

Decreases

What does the graph of glucose concentration vs. enzyme activity look like?

Some people become diabetic even though they have pancreatic β cells that make insulin:

Type II diabetes

One class of type II occurs in people younger than usual (

Mature onset diabetes in the young (MODY)

MODY is based on a ______ mutation in one of several genes, but commonly a mutation in ___________.

Single mutation to glucokinase

How does glucokinase deficiency cause MODY?

Glucokinase activity regulates the rate of glycolysis that in turn regulates insulin secretion

Glucokinase and hexokinase are isozymes that catalyze the same reaction. Which of the following does NOT describe relevant facts about the two?

Glucokinase is found in brain and pancreatic β cells, while hexokinase is found everywhere

Red cells lack mitochondria, so they rely on __________ for ATP production.

Glycolysis

Glycolysis provides muscle the energy for ________.

Exercise

Aerobically or anaerobically, glycolysis produces energy in the form of ___.

ATP

What is the first phase of glycolysis?

Energy investment phase

The first phase of glycolysis uses _ ATP to generate what?

2 ATP → 2 phosphorylated 3-carbon intermediates (G3P)

What happens to G3P?

Oxidized and phosphorylated by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to form 1,3-biphosphoglycerate

Glyceraldehyde 3P dehydrogenase shows ________ cooperativity.

Negative cooperativity

What is NAD+?

Nicotinamide adenine dinucleotide - a coenzyme from Vitamin B3 that functions as an electron carrier

NAD+ reversibly accepts _e- and _H+ from substrate

2e- and 1H+

What is niacin?

Vitamin B3

What happens when you have a niacin deficiency?

Diarrhea, dermatitis, dementia

What happens when you run out of NAD+ (i.e. under anaerobic conditions)?

Lactate dehydrogenase (LDH) regenerates oxidized NAD+

What are:

Glycogen, ribose, NADPH

Glucosamine

Triglycerides, phospholipids

NADH

2,3-bisphosphoglycerate

Serine

Alanine

Important glycolysis metabolites

T/F: The regulation of glycolysis occurs at steps that are close to equilibrium.

False; far from equilibrium

What does a defect in glucokinase cause?

MODY

What does a defect in pyruvate kinase cause?

Warburg Effect

What regulates hexokinase?

Inhibited by glucose-6-phosphate

What regulates phosphofructokinase I?

Inhibited by ATP

Promoted by AMP

What regulates pyruvate kinase?

Promoted by fructose,1,6,BP

What does PFK-1 do?

Converts fructose-6-P to F1,6P2

What is the key regulated step in glycolysis?

PFK-1

What is a strong inhibitor of PFK-1?

Intracellular ATP

What are allosteric inhibitors of PFK-1?

Citrate, signaling high Acetyl-CoA

The actual rate of PFK-1 is determined by the amount of a positive regulator that relieves the allosteric inhibition:

Fructose-2-6-bisphosphate

What makes fructose-2,6-bisphosphate?

Made from F6P by a second phospofructokinase (PFK2)

PFK2 can be regulated by hormones such as _______.

Insulin

Where does glucose synthesis occur mainly?

Liver and kidney

How is pyruvate kinase regulated in the liver?

+ F1,6P2

- ATP

- ALA

- PKA phosphorylation

What are the targets of toxic chemicals?

Hexokinase, GAPDH, and enolase

What inhibits hexokinase?

G6P

What can fluoride inhibit?

Enolase

What type of imaging can be done to detect metastasis?

PET imaging

Too much fluoride can cause what?

Fluorosis

What is Tauri Disease?

Glycogen storage disease VII

High protein diet may help

How many PFK isozymes are there?

3

Muscle has one specific form, RBCs have a mix of the 3 and thus have significant activity

What happens when there is a mutation in Muscle PFK I?

Easily fatigued

Can't keep pace with others

Weakness/stiffness in exercise

No rise in blood lactate in exercise

Glycolysis is the conversion of...

6 carbon glucose to 3 carbon pyruvate (aerobic conditions)

6 carbon glucose to lactate (anaerobic conditions)

What other dietary sugars are metabolized by glycolysis?

Mannose, galactose, fructose

Where is glycolysis especially important?

Brain, RBC (anemia), and skeletal muscle

What limits glycolysis?

Inorganic phosphate (Pi)

When does glycolysis require the niacin-derived coenzyme NAD+?

At the G3P dehydrogenase (GAPDH) step

Glycolysis has a direct yield of how much ATP?

2 moles of ATP / mole of glucose

Under aerobic conditions, how much more additional ATP are generated by electron transport/oxidative phosphorylation?

4-6

What are the 3 irreversible steps of glycolysis?

Glucokinase/hexokinase (beta cells)

Phosphofructokinase (many tissues)

Pyruvate kinase (liver)

Which intermediates are used for synthesis?

Amino acids (serine/alanine)

Fats

Carbohydrates (glucosamine)

Nucleic acids (ribose and bases)

What are the targets of toxic chemicals?

Hexokinase (2-deoxyglucose)

GAPDH (arsenics)

Enolase (fluoride)

Where does glycolysis occur?

Cytoplasm

PET scanning works because the product of the __________ reaction accumulates.

Hexokinase

A patient's red cels demonstrate a high level of 2,3 bisphosphoglycerate. Which glycolytic enzyme do you suspect is defective?

Pyruvate kinase

If 2,3 bisphosphoglycerate is accumulating where must the block be?

Downstream (pyruvate kinase)

Red cells have lactate dehydrogenase primarily so that:

They can regenerate NAD+ to keep glycolysis going under anaerobic conditions