Exam 2 biochemistry Pentose Phosphate Pathway /Glucogen/Fats

Pentose Phosphate Pathway

Another way to OX glucose to CO2
Converts G6P to ribose 5 phosphate via oxidative pathway (CYTOPLASM)

Glycolysis for PPP

Produce ATP and carbon fragments to oxidize Co2 in citric acid cycle

Pentose phosphate pathway reducing power

NADPH, and CO2 is molecular precursors

Purpose of Pentose Phosphate Pathway

alternative way OX glucose
Produce pentose for nucleotide synthesis
Produce NADPH

Pentose phosphate Oxidative

Produce 2 NADPH and Pentose Phosphates

Pentose phosphate NONoxidative

Produce phosphorylated sugars
Converts pentose phosphate in excess back to glycolic intermediates (F6P, G6P, GAP)

Transketolase and Transaldolase

First Step of PPP

Irreversible and rate determining step (Oxidative phase)
G6P+ NADP+ to 6 phosphoglucono-s-lactone + NADPH + H
Enzyme: G6P dehydrogenase

Reversible/Oxidative PPP

Irreversible/Nonoxidative PPP

First step PPP Picture

PPP and Glycolysis

Both START with G6P
- Coordinately controlled

4 modes of operation PPP

1- more ribose 5 phosphate than NADPH
2- needs for NADPH and ribose 5 phosphate balanced
3- more NADPH needed
4- BOTH nadph and ATP required

Reactive oxygen species (ROS) defense system

G6P dehydrogenase and Glutathione
Generated by oxidative metabolism and damage macromolecules

Glutathione=Antioxidant

Reduced version= tripeptide with SH group, reduces ROS
Oxidized version regenerates reduced version

Reduced glutathione is regenerated by

NADPH
Oxidized glutathione reduced to reduced glutathione using NADPH depending enzyme glutathione reductase

NADPH regenerated by G6P dehydrogenase

maintains levels of glutathione to combat oxidative stress(ros), proper reducing environment in cell

• Antioxidants

PICTURE OF PPP

G6P dehydrogenase deficiency (dh is dehydrogenase)

Human genetic disease

• Hemolytic anemia from lack of NADPH production

Lack of NADPH production

Results in increased reactive oxygen species and oxidative damage 

• Fava beans, infections, drugs trigger hemolytic anemia 

• Antimalaria drugs and sulfa drugs

Four fates of G6P

1- Metabolized by glycolysis
2- Converted into glucose by liver/kidneys, release into bloodstream
3- Enters PPP to yield NADPH and ribose derivative
4- Synthesize glycogen in liver/kidneys

Liver Glycogen

Controlled release of Glucose: maintain blood glucose
- Glycogen degradation/synthesis happens with G6P-tase (irreversible)

Muscle Glycogen

Sudden energy source (exercising)
-Glycogen metabolized without O2
-Glycogen synthesis/degradation don’t go through G6P-tase (so its in both process)

Glycogen degradation

Releases energy (exergonic) where glucose released from glycogen (NO ATP USED)

• Glycogen break down in liver/muscle

Glycogen synthesis

Consume energy (endergonic) 1 ATP and 1 UTP consumed per glucose 

Glycogen degradation enzyme activity

Degrade glycogen
Remodel glycogen
Isomerize G1P to G6P
release glucose in liver 

Glycogen degradation enzyme step 1

Glycogen phosphorylase-Reversible

• Cleaves glycogen by adding Pi called phosphorolytic cleavage of glycogen and releases G1P

• Prosthetic group: Pyridoxal phosphate

  • N to N-1

Glycogen degradation enzyme step 2

Debranching enzyme-Irreversible

• Phosphorylase cleave a-1,4glycosidic bonds until 4 residues only

• Debranching enzymes transferase activity shifts from 3 glucosyl residue from branches

• Debranching enzyme a-1,6-glucosidase activity degrades its bond, releasing free glucose
  

Glycogen degradation enzyme step 3

Phosphoglucomutase- reversible

• Enzyme converts G1P into G6P and phosphoserine catalysis this step 

• Both glycogen metabolism and galactose catabolism

Glycogen degradation enzyme step 4

G6P-tase- Irreversible

• Liver: release free glucose

• Muscle: Glycogen degradation ends with G6P

Phosphorolysis advantage

1- Conserve energy

• Product G1P into G6P without ATP in phosphoglucomutase step

2-Mobilization

• glycogen phospho. quick because no Pi in cell

3-Phosphorylated intermediate stays in cell

• G6P and G1P charged, unable diffuse out of membrane

Glycogen regulation in liver/ muscle

• Glycogen breakdown regulated in phospr. step as allosteric enzyme

• T and R state phosphorylated, turn T or R on or off

• Phosphorylated in R state (ON when cell needs energy)

Liver maintains

Glucose homeostasis, while muscle use glycose to produce energy 

Glucagon vs Epinephrine needed

stimulate liver-glycogen breakdown in low blood glucose vs enhances glycogen breakdown in muscle/liver for muscle contraction

Very active

Hormones bind to specific receptors

Signal transition pathway, activation
Turn off: hormones stopped, PP1 (insulin activated) removed phospho. group from kinase 

Glycogen degradation and synthesis by blood glucose 

Covalent modification (phosphor.) and hormones (insulin, epineph, glucagon) 

• Synthesis inhibit: by hormones for glycogen breakdown

• insulin stimulates synthesis: inactivate synthase kinase, PP1 activates, insulin increases 

• Protein kinase A controls glucagon 

Fatty acids

Carboxylic acid-CH3-CH2-Methyl group

Stored as triacylglycerol: 3 fatty acids to 1 glycerol in adipose tissue

Triacylglycerol form lipid droplets in stomach

Then products carried into intestinal epithelium (absorption)
reformed and packaged into chylomicrons (into tissue)

Dietary triacylglycerols digested by pancreatic lipase

Small intestine after emulse bile salts
absorbed into intestine cells and packaged into chylomicrons for storage in adipose tissue

Endogenous triacylglycerols are broken down by lipolysis

In adipose tissue during exercise (fuel)
Hormone sensitive lipase and adipocyte triag. lipase hydrolyze and store triag. to glycerol and fatty acids
Triggered by hormones
Faty acids travel to tissue for energy (b-oxidation), to liver for GNG

Endogenous triag catabolized stage 1

Lipolysis

• Hormones activate protein kinase A

• Hormone sensitive lipase activated

• activate adipocyte triag. lipase to break down lipids

• Into fatty acids to create glycerol 

Endogenous triag catabolized stage 2

Activate and transport Catabolism

• Fatty acid link to CoA by CoA synthetase

• Transferred to carnitine by carnitine acyltransferase

  • Glycerol to DHAP

Endogenous triag catabolized stage 3

Beta Oxidation (fatty acid degrade)

• Oxidize, hydrate, oxidize, thiolysis (4 steps) to shorten fatty acids by 2 carbons each round

Activate fatty acids to CoA

• In cytoplasm by Acyl Coa synthetase (ligase)

• Fatty acid + CoA + AtP —> Fatty acyl CoA, AMP, Pi

• IRREVERSIBLE

Transport fatty acids by Carnitine shuttle

Step 1: Carnitine acyltransferase 1

• outer mito membrane

• inhibited by malonyl CoA

• Fatty acyl group from CoA to carnitine

Step 2: acyl carnitine translocase

• Acyl carnitine in and carnitine out (inner membrane)

• no atp

Step 3: Carnitine acyltransferase 2

• INNER mito membrane

• Fatty acyl group from CoA to carnitine

Beta Oxidation 4 steps

1-Oxidation dehydrogenation- irreversible

• Acyl CoA dehydrogenase (redox)

2-Hydration-reversible

• Enoyl CoA hydratase (lyase)

3-Oxidation

• L-3-hydroxyacyl CoA dehydrogenase (redoc)

4-Thiolysis

• B-Ketothiolase (transferase)

How many ATP for complex oxidation of fatty acid

2 atp activation

• 1 acetyl Coa: 10 atp

• 1 fadh2: 1.5 atp

• 1 nadh: 2.5 atp

Unsaturated fatty acid breakdown

Monounsaturated odd number double bonds

• Cis 3-enoyl CoA Isomerase coverts cis to trans

Polyunsaturated even number double bonds

• same isomerase+ 2,4 dienoly CoA convert fatty acid from trans to intermediate in beta oxidation

Synthesis(anabolism) of ketone bodies

• GNG dominates with diabetes, Acetyl CoA cannot enter tricarboxylic acid cycle

  • Forces to create ketone bodies, acetoacetate and d-3-hydroxbutryrate

• D-3-hydroxybuturate formed through reduction acetoacetate 

• synthesis in liver

Degradation (catabolism) of ketone bodies

• Fasting state to feed heart, kidneys, brain

• Hydroxybutyrate oxidized to form NADH and acetoacetate

• then metabolized into 2 acetyl CoA

• degrade in mitochondria 

Glycogen Synthase

Transiter glucose from UDP to glycogen
Glycogenenin: catalyze formation of a-1,4-glucose using UDP until 10-20 units formed

Branching enzyme

Catalyze branching glycogen chain forming 1-6 linkage every 12-13 glucose residues
cleaves a-1,4- linkage to transfer 7 glucose residues for a-1,6- linkage