pentose phosphate Flashcards
Names of pentose phosphate pathway
- pentose phosphate pathway
- Hexose Monophosphate (HMP) shunt
Purposes of pathway
- generation of NADPH
- Generation of the 5-carbon sugar, ribose. to be used in the synthesis of nucleotides
- can make both OR either. depends on needs of the cell
- NO ATP IS PRODUCED OR USED
Dehydration of Glucose 6-P
-step 1 Enzyme: Glucose 6-phosphate dehydrogenase (G6PD) -RATE LIMITING -IRREVERSIBLE -NADP+ is required coenzyme -NADPH is potent competitive inhibitor -expression is UPREGULATED by insulin -PRODUCES FIRST NADPH -flux through the pathway increases in absorptive state
Hydrolysis to 6-phosphogluconate
-Step 2
Enzyme: 6-phosphogluconolactone hydrolase
-IRREVERSIBLE
-NOT rate limiting
Oxidative decarboxylation of 6-phosphogluconate
Enzyme: 6-phosphogluconate dehydrogenase
- IRREVERSIBLE
- PRODUCES 1 NADPH
- makes ribose 5-phosphate by removing the carbon
oxidative and nonoxidative steps
1-3=oxidative, irreversible
4-8=nonoxidative, reversible
Nonoxidative reversible reactions purose
- interconverts sugars with 3 7-C atoms
- permits synthesis of ribose 5-P used for nucleotide production
Nonoxidative reversible reactions mechanism
Enzyme: Transketolase
- requires TTP(from thiamine)
- important in diagnosing thiamine dificiency
- done by measurement of its activity in RBCs
- TTP is supplied EXO so there is no thiamine intracellularly
Differences between NADPH and NADH
- Everything is the same, but NADPH has a phosphate on sugar
- both are electron carriers BUT NADH accepts and can donate to complex 1 in ETC
- NADPH donates electrons to biosynthetic pathways
- FUNCTIONS ARE NOT INTERCHANGEABLE
NADPH functions
- electron donor for the “reductive” biosynthesis of fatty acids, cholesterol, and steroids
- electron donor for the neutralization of reactive oxygen species
- provides reducing equivalents for CYT P450 Monooxygenase
- phagocytosis
- substrate for synthesis of nitric oxide
What are the two functions of cyt P450 monooxygenase?
- biosynthesis of steroids(mitochondrial system)
2. detoxification of xenobiotics in liver (microsomal system)
Reactive oxygen species
-produced during aerobic metabolism, through reactions with drugs and toxins, when levels of antioxidants are diminished
increased levels of ROS can…
- damage proteins and lipids
- lead to apoptosis
NADPH Role in Neutralization of ROS
Tripeptide: gamma-Glutamylcysteinglycine:G-SH
- Glutathion is the major antioxidant system
- NADPH donates electron (reduced) to GSH and free radical turns into water and is no longer dangerous
- then oxidized to GSSG and it repeats
Monooxygenase
-an enzyme that will incorporate 1 oxygen atom from molecular oxygen (creating an OH) group with the other oxygen being reduced to water
Mitochondrial system and NADPH
- inner mitochondrial membrane
- in steroidogenic tissues(placenta, ovaries, testes, adrenal) uses NADPH for synthesis of steroids
- in liver: uses it to synthesize bile acids and Vitamin D3(digestion of lipids)
- in kidney: converts vitamin D3 to its active form
Microsomal system and NADPH
- smooth ER and liver cells
- detoxification of drugs, toxins, and other chemicals
- makes OH group that activate or inactivate drugs, make more soluble, , provide a reactive group for further attachment
NADPH and phagocytosis
- in white blood cells: neutrophils and macrophages(produced from monocytes)
- generation of free radicals to aid in killing things
MPO system
-combination of NADPH oxidase and myeloperoxidase are used to generate the oxygen free radicals
NADPH oxidase deficiency
- causes chronic granulomastous disease(CGS)
- cant kill bacteria so they always have infections
- bacteria is trapped from the rest of the body, but it wont die
Nitric oxide
- synthesized from arginine, oxygen, and NADPH
- NOT NO3(laughing gas)
- very short life
- very reactive
- it is a gas and can diffuse into cells easily
NO and NADPH
Enzyme: NO synthase(3 enzymes that are products of different genes)
- nNOS:neural tissues
- eNOS: endothelial cells
- iNOS: inducible
NO enzymes and expression
- nNOS and eNOS are constitutively expressed at constant levels
- iNOS is only expressed under certain conditions
Biological activity of NO
- smooth muscle relaxant
- nitroglycerin action is converted into NO to relax smooth muscle
- used by macrophages to generate free radicals for phagocytosis
- inhibits platelet aggregation
- functions as a NT
- considered a short lived secondary messenger
G6PD
- inability to detoxify oxidizing agents
- gene is on X chromosome so boys more likely to get it
- ONE OF THE MOST COMMON SINGLE GENE DISORDERS WORLDWIDE(400 million affected)
- 1/4 males are affected
- african and asian more likely
- some protection against malaria
- 11% amond blakcs
G6PD precipitating factors
- only symptomatic when experiencing oxidative stress
- Infection: oxygen radicals generated by marcophages
- drugs that produce an oxidative stress(chemo)
- fava beans(not all for this)-favism
Classes of G6PD
class 1-very severe- (chronic)less that 10% enzyme activity class 2:severe(episodic)-less than 10% class 3: moderate(10-60% of enzyme activity class 4: none-greater than 60% of enzyme activity
Clinical manifestation of G6PD
- almost exclusively in RBC as an episodic hemolytic anemia in adults
- neonatal jaundice in newborns
- effects on other organs due to hemolytic anemia
- shorten lifespan in people with severer form
WHY IN RBC???
- the only pathway to make NADPH is HMP
- other cell types have other pathways
- RBC do not have nucleus so they cannot synthesize more G6PD to replace missing enzyme
- most mutations that result in the deficiency affect the stability of the enzyme
- most patients will be okay by making new RBC
Heinz bodies
- characteristic of G6PD deficiency
- found in RBC
- precipitates of oxidized hemoglobin
Hemolytic anemia
- seen with G6PD deficiency AND step 10 of glycolysis(PDH)
- Heinz bodies are only found with G6PD deficiency
