Hexose Monophosphate Pathway Flashcards
The hexes monophosphate pathway(HMP) is also called …
- pentose phosphate pathway
- hexose monophosphate shunt
- 6-phosphogluconate pathway
What 3 pentose phosphates are generated by the HMP?
- Ribose 5-phosphate. (Required for synthesis of RNA and DNA)
- Ribulose 5-phosphate
- Xylulose 5-phosphate
Where are the HMP enzymes located?
In the cytosol of of all cells
HMP is an alternate route for the …
Oxidation of glucose
When glucose is used for storage, what does it become?
Glycogen, starch, sucrose
What does glucose become when oxidized by the pentose phosphate pathway?
Ribose 5-phosphate
What are the key functions of the HMP pathway?
- generation of NADPH
- Generation of pentose, e.g. ribose 5-phosphate for nucleotide biosynthesis
- Interconversions of dietary carbohydrates into glycolysis/gluconeogenesis intermediates
What are the primary tissues of of HMP?
- Liver, Adipose tissue, lactating mammary glands
- adrenal cortex, ovaries, Testes, placenta
- Erythrocytes
- White blood cells and macrophages
- Thyroid
Discuss the Liver, Adipose tissue, lactating mammary glands as primary tissues of HMP
Liver, Adipose tissue, lactating mammary glands- NADPH provided for fatty acid biosynthesis
Discuss adrenal cortex, ovaries, Testes, placenta as primary tissues of HMP
adrenal cortex, ovaries, Testes, placenta- NADPH provided for synthesis of steroid hormones- hydroxylation reactions
Discuss erythrocytes as a primary tissue of HMP
Erythrocytes- NADPH provided for the reduction of glutathione as a protection against oxidative damage
Discuss White blood cells and macrophages as primary tissues of HMP
White blood cells and macrophages- NAPDH provided for killing phagocytosed bacteria
Discuss the thyroid as a primary tissue of HMP
Thyroid -NADPH as a coenzyme for the synthesis of thyroid hormone
What are phases of HMP?
- Oxidative phase
- Nom-oxidative phase
Explain the characteristics of the oxidative phase
- reactions are irreversible
- forms NADPH and pentose phosphate, ribulose-5-P
- Enzymes are dehydrogenases
- Reaction Catalyzed by G-6PDH is the major regulatory site for the entire HMP
- Glucose 6-phosphate + 2NADP+ + H2O —> ribulose 5-phosphate + CO2 + 2NADPH + 2H+
Give the characteristics of non-oxidative phase of HMP
- reactions are reversible
- Results in the formation of ribose 5-p for nucleic acid biosynthesis
- interconversion of sugars resulting in the formation of glycolytic intermediates- feed to glycolysis/gluconeogenesis
- Enzymes are trans ketolase and transaldolase
Describe the events of the 1st step oxidative phase of the HMP pathway
Glucose 6-phosphate converted to 6-phosphogluconate
Enzymes involved: glucose 6-phosphate dehydrogenase and 6-phosphogluconolactone hydrolase
-reduction of H2O + NADP+ —> NADPH + H+
Describe the 2nd step of the oxidative phase of the HMP phase
6-phosphogluconate is converted to ribulose 5-phosphate + CO2
Enzyme involved: 6-phosphogluconate dehydrogenase
Decarboxylation yields CO2
What are the products of the oxidative phase of the HMP pathway?
- Reduction of NADP+ —> NADPH + H+ (2)
- A decarboxylation, yielding CO2
- The product is ribulose-5-P
What are the regulators of G6P DH?
- Allosterically stimulated by NADP+
- Inhibited by NADPH
-Activated by insulin- up regulation:
Increase of amount of enzyme
What is the rate limiting(committed ) step of the oxidative step of the HMP pathway?
Glucose 6-phosphate(6C) converted to 6-phosphogluconolactone
Enzyme: glucose 6-phosphate dehydrogenase
NADP+ —> NADPH
Walkthrough the enzymes involved in the oxidative phase of HMP
- Rate limiting step :Glucose 6-phosphate- (6C) converted to 6-phosphogluconolactone
Enzyme: glucose 6-phosphate dehydrogenase
NADP+ —> NADPH
- 6-phosphogluconolactone(6C) —> 6-phosphogluconate(6C)
Addition of water
Enzyme: lactonase
- 6-phosphogluconate (6C) —>ribulose 5-phosphate(5C)
Enzyme: 6-phosphogluconate
Produces CO2
- NADP+—>. NADPH
What is the function of lactonase?
6-phosphogluconolactone(6C) —> 6-phosphogluconate(6C)
Addition of water
Enzyme: lactonase
- The lactonase intermediate is unstable
- Lactonase catalyzes ring opening
- It acts as a hydrolase- H2O
What is the function of 6-phosphogluconate dehydrogenase?
6-phosphogluconate (6C) —>ribulose 5-phosphate(5C)
Enzyme: 6-phosphogluconate
Produces CO2
- NADP+—>. NADPH
- Catalyzes a 2nd oxidative reaction
- An unstable B-keto acid intermediate
- NADP+ and Mg2+ are required
- Decarboxylation —> a keto pentose I.e. ribulose-5-P
What are the products of the Non-oxidative phase
Glyceraldehyde 3-P
And
Fructose 6-P
Which phase of the HMP is the link to glycolysis/gluconeogenesis?
Non-oxidative phase
What is the non-oxidative phase of HMP pathway?
A pool of pentose-P interconversions
What is the 1st step of the Non-oxidative phase /4 the step of the HMP pathway?
Ribulose 5-phosphate converts to ribose 5-phosphate
Enzyme: ribose 5 phosphate isomerase
2 carbons are transferred in transketolase
What is special about tissues which use NADPH than ribose 5-phosphate?
In tissues requiring primarily NADPH rather than ribose 5-phosphate, the pentose phosphates can be recycled into glucose 6-phosphate
What is reductive biosynthesis?
reactions in fatty acid synthesis and synthesis of steroid hormones
What is cytochrome P450?
A coenzyme for reductive biosynthesis
What are the coenzymes of NADPH?
Cytochrome P450
Glutathione reductase
NADPH oxidase
What is glutathione reductase?
A coenzyme of reductive biosynthesis- to reduce oxidative stress via reduction of H2O2
What is NADPH oxidase?
A coenzyme of reductive biosynthesis-immunity via phagocytosis of pathogens by WBCs
What processes produce NADPH?
- Irreversible oxidative phase of the HMP pathway
- NADP+ dependent malate dehydrogenase (except for erythrocytes)
What processes consume NADPH?
- fatty acid synthesis
- steroid synthesis
- drug metabolism
- glutathione reduction
- Generation of super-oxide in phagocytes by NADPH oxidase
What can result from the NADPH oxidase mutations?
Mutations in gene for NADPH oxidase lead to decrease enzymatic activity
This causes chronic granulomatous disease
What is nitric oxide synthesis?
Generation of nitric oxide and reactive oxygen species by phagocytosis
How does NADPH prevent oxidative stress?
It reduces glutathione via glutathione reductase
Which converts reactive H2O2 into H2O via glutathione peroxidase
If absent, the H2O2 would be converted to hydroxyl free radicals which can attack the cell
Describe the formation reactive oxygen species
Reduction of molecular oxygen in a series of one-electron steps yields superoxide, hydrogen peroxide, hydroxyl radical, and water
The intermediate, activated forms of oxygen are known as reactive oxygen species (ROS)
Give the reactions required to form ROS intermediates
Oxygen +e- —> superoxide (oxygen molecule radical)
Superoxide + e- —> H2O2
H2O2 + e- —> hydroxyl radical OH-⏺
Hydroxyl radical + e- —> H2O
What is the effect of reactive oxygen species on cells?
Environmental insults causes cellular damage
Damage to lipids, proteins, nucleic acids, and carbohydrates
This leads to cell damage and cell death
Describe glutathione (GSH) as an antioxidant enzyme
Reduced glutathione (GSH) protects the cell by destroying hydrogen peroxide and hydroxyl free radicals
Regeneration of GSH from its oxidized form (GS-SG) requires the NADPH produced in the glucose 6-phosphate dehydrogenase reaction
Give some examples of antioxidants scavengers(clearing of ROS)
Vitamin C-ascorbic acid
Vitamin E- tocopherols
Vitamin A- Carotenoids
What is the function of Cytochrome P-450 Monooxygenase systems in the mitochondrial system ?
Important in the synthesis of steroid hormones from cholesterol
What is the function of Cytochrome P-450 Monooxygenase systems in the microsomal system ?
Important in detoxification of toxins, pesticides, organic compounds, drugs
Give the reaction of Cytochrome P-450 monooxygenase systems
Substrate R may be steroid, drug, or other chemical + O2 + NADPH + H+( NADPH acts as a reducing equivalent)
Cytochrome. P 450
Products: ROH(hydroxyl group created + H2O + NADP+
How does NADPH yelp immunity?
- Phagocytosis of pathogens
- Leukocytes, macrophages, neutrophils utilize oxygen-dependent mechanisms to destroy bacteria (oxidative burst)
- Requires the generation of superoxide as well as other reactive oxygen species
- NADPH oxidase in parts responsible for this production
What happens during NADPH oxidase deficiency ?
Deficiency of NADPH oxidase causes chronic granulomatous disease characterized by severe persistent infections
Explain the pathway during phagocytosis to explain NADPH importance to immunity
- Attachment of pathogen to a phagocytocytic cell
- Ingestion of organism
- Destruction of the microorganisms
- NADPH + O2 —> O2-(RADICAL) + NADP+ (catalyzed by NADPH oxidase/ this is the respiratory burst
- O2- (radical) either spontaneously or superoxide dismutase, is converted to hydrogen peroxide
- Myelo peroxidase absorbs Cl- to create OCl- or converts hydrogen peroxide to OH(radical) be converting Fe3+ to Fe2+
- OCl- and OH(radical) together make hypochlorite acid which destroy bacteria
Infections result in….
Increased production of oxidants
Where is nitric oxide synthesized?
-Synthesized in endothelial cells (vascular endothelial cells and lymphatic endothelial cells), and neural tissue
What are the coenzymes of NO synthase?
- Flavin mononucleotide (FMN)
- Flavin adenine dinucleotide (FAD)
- heme
- tetrahydrobiopterin
Give the reaction of NO synthesis
L-Arginine + O2 + NADPH + H+—> NADP+ +NO + L-citrulline
Enzyme: NO synthase
How does NO help with relaxation of smooth muscle?
Synthesized NO diffuses into vascular smooth muscle and activates cytosolic guanylate cyclase to form cyclic guanosine monophosphate (cGMP), eventually resulting in smooth muscle relaxation
How do vasodilators like nitroglycerin and nitroprusside cause smooth muscle relaxation
Vasodilators such as nitroglycerin and nitroprusside are metabolized to NO resulting in smooth muscle relaxation and lowering of blood pressure. NO is considered an endogenous vasodilator
What are the functions of Nitric oxide (NO)?
- relaxes smooth muscle
- prevents platelet aggregation
- prevents platelet aggregation
- neurotransmitter in the brain
- mediates tumoricidal and bacterial actions of macrophages
How can NO help with macrophages?
Activated macrophages form oxygen free radicals that combine with NO to form compounds more bactericidal than NO itself
