Lecture 27: G6P fates: PPP/Glycogen Metabolism

What happens if you have a lot of glucose-6-phosphate in the cell

Once glucose becomes glucose-6-phosphate after step 1 of glycolysis:

it cannot leave the cell because the phosphate group is negatively charged and the membrane is nonpolar

Why glycolysis may stop

cell has a lot of ATP:

• the body is efficient and stingy

• if energy is not needed, the body will not keep making more

• phosphofructokinase is inhibited by ATP

• so glucose-6-phosphate cannot keep moving forward through glycolysis

Two possible fates of excess glucose-6-phosphate

1. Pentose phosphate shunt

2. Glycogen storage

1. Pentose phosphate shunt

this pathway makes ribose-5-phosphate which is used to make DNA and RNA and NADPH which is used for fatty acid synthesis

anabolic

2. Glycogen storage

If the liver needs more glucose reserves: glucose-6-phosphate can be used to make glycogen

body stores one day worth of glucose as glycogen

high ATP inhibits

glycolysis and krebs cycle

so pentose phosphate shunt and glycogen storage occur

Main functions of pentose phosphate shunt

1. Making ribose for nucleotide biosynthesis

2. Making NADPH

3. Producing intermediates that go back into glycolysis

1. Making ribose for nucleotide biosynthesis

ribose → RNA

ribose can also be turned into deoxyribose → DNA

2. Making NADPH

NADPH provides reducing power used to make fatty acids from acetyl-CoA

3. Producing intermediates that go back into glycolysis

fructose-6-phosphate and glyceraldehyde-3-phosphate

So it is a shunt because it leaves glycolysis and then rejoins it

both NAD and NADP have

a nicotinamide-containing nucleotide, an adenosine-containing nucleotide, and connected by phosphate

-active redox part is the nicotinamide ring

Difference between NAD and NADP

NADP has an extra phosphate group at carbon 2 of the ribose of the adenosine part

Why the difference matters

NADH helps produce ATP

NADPH helps with anabolic processes like fatty acid synthesis

-helps regulate metabolism efficiently

Oxidative phase of pentose phosphate shunt

glucose-6-phosphate (6 carbons) → ribulose-5-phosphate (5 carbons)

-decarboxylation bc CO2 released

-3 oxidation phase

first oxidation of oxidative phase

Glucose-6-phosphate is oxidized to a ketone-containing intermediate

NADP+ reduced to NADPH

second oxidation of oxidative phase

another oxidation occurs, another NADPH is formed and CO2 is released

For each glucose-6-phosphate going through the oxidative phase:

2 NADPH, 1 CO2, and 1 ribulose-5-phosphate

Products of oxidative phase

3 ribulose-5-phosphate, 3 CO2, and 6 NADPH

oxidative phase reaction description

2 oxidations and 1 decarboxylation per glucose-6-phosphate

Nonoxidative phase of pentose phosphate shunt

carbon rearrangement in sugars resulting in ribose-5-phosphate, 2 fructose-6-phosphate, and 1 glyceraldehyde-3-phosphate

If ATP is high and G6P is high

If the liver does not have enough glycogen reserves: glucose-6-phosphate will be used to make glycogen

Why glycogen reserves matter

if you are starving or fasting, the body must still provide glucose to the brain

Liver role

stores glycogen and responsible for maintaining blood glucose

Muscle role

stores some glycogen and spends it on itself during fight-or-flight

Blood glucose target

The liver is responsible for maintaining 5 millimolar glucose in the blood

too low → hypoglycemic

too high → hyperglycemic

Glycogen synthesis pathway

Step 1: G6P → G1P

Step 2: G1P + UTP → UDP-glucose + pyrophosphate

Step 3: UDP-glucose + glycogen chain → longer glycogen + UDP

glycogen synthesis step 1: glucose-6-phosphate → glucose-1-phosphate

enzyme phosphoglucomutase moves phosphate from carbon 6 to carbon 1

glycogen synthesis step 2. Reaction of Glucose-1-Phosphate with UTP to form UDP-glucose

2 favorable factors UTP hydrolysis and pyrophosphate release bc of le chateliers principle and entropy

glycogen synthesis step 3: UDP-glucose + glycogen chain → longer glycogen + UDP

enzyme glycogen synthase adds glucose units to a growing glycogen chain

-energy coupling

Breakdown of Glycogen (Glycogenolysis)

enzyme glycogen phosphorylase breaks one glucose unit of glycogen and adds phosphate to give glucose-1-phosphate

Two types of hormones

1. Lipid-soluble

2. Water-soluble

Lipid-soluble hormones

lipid/fat based but cant’ move easily through the bloodstream on their own so they require special carrier proteins in blood

Lipid-soluble hormones examples

steroid-derived hormones, testosterone, estrogen, cortisol, and thyroid hormones

mechanism of Lipid-soluble hormones

they can easily cross the cell membrane, the nuclear membrane, and and can interact with DNA/genes

-slower but long lasting effect

Water-soluble hormones

proteins or peptides that can move easily through the bloodstream but they can’t cross the cell membrane

Water-soluble hormones example

epinephrine, insulin, and glucagon

Water-soluble hormones mechanism

they bind to a membrane receptor which activates a secondary messenger (cAMP), cAMP goes downstream and phosphorylation happens and the enzymes gets activated or inactivated

effects of Water-soluble hormones

faster, short lived, and effect fades quickly

Insulin

a protein/peptide hormone produced by beta cells of the pancreas and is secreted when glucose is high and directs glucose toward glycogen storage

-water soluble

insulin’s active form

an A chain, a B chain, and intra- and inter-chain disulfide bonds

Glucagon

produced by alpha cells of the pancreas and is secreted when blood sugar is low, it works to increase glucose concentration

-water soluble

Epinephrine / Adrenaline

derived from tyrosine but has enough hydroxyl groups to be water-soluble and is secreted by the adrenal medulla

secreted during fight-or-flight