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1021 HMP Shunt Pathway Dr Lieberman
UC MED 2015 1021 HMP Shunt Pathway Dr Lieberman
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Medical
10/20/2011

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Term
Net reaction of oxidative reactions
Definition
G6P + 2 NADP+ + H2O --> Ribose 5-phosphate + 2 NADPH + CO2 + 2H+
Term
Difference between oxidative and non-oxidative reactions
Definition
Oxidative reactions generate NADPH while the non-oxidative reactions allow five carbon sugars to be converted to six carbon sugars, using reversible reactions
Term
What diseases are caused by thiamine deficiency (Vit B1)
Definition
Beriberi and Wernicke-Korsakoff syndrome
Term
Beriberi
Definition
Caused by thiamine deficiency. Has two main types:
Fluid retention (wet beriberi – cardiovascular system) Heart can't pump enough.
Pain, paralysis (dry beriberi – nervous system can't maintain proper ion gradients).

Fluid retention (wet beriberi – cardiovascular system)
Pain, paralysis (dry beriberi – nervous system)
Term
Wernicke-Korsakoff syndrome
Definition
Primarily seen in alcoholics
Alcohol impairs thiamine absorption
Neuronal dysfunction (lack of energy due to lack of pyruvate dehydrogenase activity)
Term
How to test for thiamine deficiency
Definition
Can test for thiamine deficiencies by measuring transketolase activity in red blood cells
Term
What is significant about Ru5P in oxidative pathway
Definition
Ru5P is NOT a substrate for either TK or TA, so it must be converted to either X5P or R5P for further metabolism
Term
How is HMP Shunt Pathway regulated?
Definition
The [NADP]/[NADPH] ratio is important. An increase in [NADP] activates G6PDH, leading to increased NADPH production. High ratio, high activity. Under normal conditions the ratio is 0.014, at which the enzyme is inactive. Needs of the cell also dictates the flow of both the oxidative and non-oxidative rxns

Term
What happens when Cell Requires more R5P than NADPH?
Definition
Use TK and TA to generate R5P from F6P and G3P, bypassing oxidative steps. ATP is required by the PFK-1 reaction, in which F6P is converted to F1,6BP

Term
What happens when The cell needs equal amounts of NADPH and R5P?
Definition
Use only the Oxidative Reactions of the Pathway. If the R5P is rapidly utilized, its concentration will be too low to be acted on by TK or TA.
Term
What happens when cell Requires more R5P than NADPH?
Definition
The strategy for this case is to go through the oxidative reactions to form NADPH and Ru5P, and then to utilize the non-oxidative reactions, and gluconeogenesis, to convert the Ru5P to glucose.
Term
What happens when Cell Needs NADPH and Carbons for Biosynthesis?
Definition
The basic strategy is to take G6P through the oxidative reactions to generate NADPH and Ru5p.
The Ru5P is then used to produce pyruvate by combining TK, TA reactions with that of glycolysis.
Term
Quick summary of directions of HMP Shunt Pathway
Definition
R5P formation in the absence of NADPH production: use only the non-oxidative pathways.
Both NADPH and R5P required: Use only the oxidative reactions.
Only NADPH is required: regenerate G6P from the Ru5P produced.
Need both NADPH and pyruvate for biosynthesis: Use HMP shunt and glyoclysis.



Term
Cells primarily affected by G6PDH deficiency and why
Definition
Red blood cells b/c they have no mitochondria, so NADPH cannot be generated in the mitochondria. Mitochondria contain an enzyme, transhydrogenase, which will convert NADH + NADP+ into NAD+ and NADPH in a reversible reaction. Without transhydrogenase, the only means of producing NADPH is by the HMP shunt oxidative reactions (red cells lack malic enzyme activity)
Term
Consequences of lack of NADPH in red blood cells due to G6PDH deficiency
Definition
As the RBC travels through the body, it is subject to various chemical attacks on the membrane, primarily oxidizing agents. Damage to the red cell membrane can lead to premature cell lysis, reduction in red blood cells, and anemia. The RBC protects itself from oxidative damage by the presence of a small peptide known as glutathione. The glutathione is normally in a reduced state, which is preferentially oxidized by the oxidizing agents instead of red cell membrane proteins. The oxidized form of glutathione is then reduced by NADPH, produced through the HMP shunt, using the enzyme glutathione reductase. Thus a dysfunctional HMP shunt would leave the red cell membrane vulnerable to oxidative damage once all the glutathione in the membrane had been oxidized.
Term
Glutathione pathway
Definition
Lack of NADPH leads to the buildup of oxidized glutathione, leading to the oxidation of membrane proteins, and lysis of the red cell. Glutathione reductase is the enzyme which will reduce oxidized glutathione.
Term
When is G6PDH deficiency seen and why
Definition
Only under conditions of oxidative stress. Under normal conditions, the reduced levels of G6PDH are sufficient for the life-span of the RBC (ie, there are not too many oxidants present in the circulation). Certain drugs (ie, anti-malarials) are oxidizing agents, so in the presence of these drugs hemolytic anemia may result
Term
What is the selective advantage of G6PDH deficiency?
Definition
resistance to malaria
Term
Reactive Oxygen Species (ROS)
Definition
Oxygen has two unpaired electrons with parallel spins, so oxygen can accept one electron at a time. This can occur during reactions which utilize oxygen as a substrate. Cofactors such as metal ions are usually required to allow one electron transfers to oxygen. Sometimes the reactive oxygen intermediates escape from the enzyme. Lipid peroxidation can result, and destroy membrane integrity.
Protein oxidation (particularly amino acids with ring nitrogens and sulfurs) can result, destroying protein function.
Term
Types of enzymes that use molecular oxygen
Definition
Oxidases and oxygenases
Term
Oxidases
Definition
Transfer electrons to oxygen, generating water or hydrogen peroxide (H2O2) (example is cytochrome C oxidase)
Term
Mono-oxygenase
Definition
Incorporate one atom of oxygen into substrate; other atom into water.
Also called hydroxylases (ex: phenylalanine hydroxylase catalyzes phe --> tyr). Usually requires a flavin derivative for one electron transfers, and a source of electrons (NADH or NADPH)
Term
Di-oxygenase
Definition
Incorporate both atoms of oxygen into the substrate. Cyclo-oxygenase (required for prostaglandin production) is an example
Term
Cytochrome P450 family
Definition
Large family of mono-oxygenases. They contain iron in a heme ring and hydroxylate a wide variety of compounds.
This is the first line of defense against many toxic compounds.
Over 100 different family members, many of which are inducible by their substrates. The enzymes require NADPH as a source of electrons, cytochrome P450 reductase (flavin containing enzyme), and cytochrome P450 to orient the oxygen to attack the substrate.
Term
Relation between ethanol, barbituates and Cytochrome P450
Definition
Barbiturates (sleeping pills) are metabolized through the P450 system (CYB2B1 and CYB2B2). This is an inducible system, so the longer an individual takes the drugs, the faster they metabolize it (due to the induction of the P450 system). Thus, a person develops tolerance to the drug, and higher doses of the drug are required to obtain the same effect. Ethanol (which induces CYB2E1) inhibits this particular P450 enzyme system. Thus, if one ingests ethanol, and then takes a high dose of drugs due to tolerance, the P450 system is inactive, and death can result from an overdose
Term
Maximum daily dose of Tylenol for an adult
Definition
4g per day for an adult; toxicity is seen at 150 mg/kg
Term
How is superoxide (O2-) generated?
Definition
In mitochondria, CoQ + O2 yields CoQ + O2- (occurs when the oxygen levels are high). In Neutrophils, NADPH oxidase catalyzes 2 O2 + NADPH yields 2 O2- + NADP+, in order to destroy engulfed bacteria in vacuoles. Escape of O2- from vacuoles can lead to damage
Term
3 main anti-oxidant enzymes
Definition
Superoxide dismutase, catalase, glutathione peroxidase
Term
Superoxide dismutase
Definition
2 O2- + 2H+ --> H2O2 + O2
Mitochondrial enzyme
Primary line of defense against superoxide. Mutated enzyme linked to familial Lou Gehrig’s disease
Term
Catalase
Definition
2 H2O2 --> 2 H2O + O2
Present in peroxisomes, neutrophils, mitochondria
Term
Glutathione peroxidase
Definition
H2O2 + 2 GSH --> GSSG + 2 H2O
NADPH required to regenerate GSH from GSSG. Present in mitochondria and red cell (cytoplasm)
Term
Glutathione: GSH and GSSG
Definition
GSH is reduced form, GSSG is oxidized form
Term
transketolase
Definition
Transketolase transfers 2 carbons between sugars, requires thiamine pyrophosphate as a cofactor, can be utilized as a measurement for thiamine deficiency and is in cytoplasm. It does not catalyze an internal oxidation-reduction reaction.
Term
transaldolase
Definition
Transaldolase requires a lysine residue at the active site, has a similar rxn as aldolase, transfers 3 carbons btwn sugars, and is found in cytoplasm. For TK and TA donor sugar is ketose. Acceptor is aldose. Fructose is example of ketose; glucose is example of aldose.
Term
Major regulated step in oxidative pathway
Definition
Glucose 6-Phosphate Dehydrogenase step (first step)
Term
Where do HMP shunt pathway and glycolysis intersect?
Definition
F6P and G3P
Term
Why can introducing oxygen to the heart after a heart attack cause more damage?
Definition
due to reduced CoQ in the mitochondrial membrane. CoQ may give electrons to random oxygen molecules, creating superoxide
Term
How tylenol can cause liver damage
Definition
Tylenol causes liver damage if too much is taken. Normally it is made more soluble and secreted in urine. Normally, small amount is made into NAPQI, a toxic intermediate that is taken care of by GST, by CYP2E1. Tylenol overdose occurs when there isn’t enough GSH to detoxify all the NAPQI. Ethanol causes alcoholics to have higher CYP2E1, which shunts tylenol to dangerous pathway. Alcoholics are given N-acetyl cysteine to shunt NAPQI to GST.
Term
Radical chain terminators
Definition
Vitamins A, C, and E. They are protective by sopping up free radicals.