Exam 3 Biochem-Lecture 26

What are alternates names for

Pentose Phosphate Pathway?

 

Hexose Monophosphate Shunt

-6-Phosphoroglucontate pathway

 

Pentose Phosphate Pathway Products include:

 

NADPH for reductive biosynthesis

-fatty acids and steroids

Ribose-5-phosphate

-Nucleic Acids

Glycolytic Intermediates

         -glyceraldehyde-3-phosphate

         -Fructose-6-phosphate

Higher requirement for NADPH than ribose-5-phosphate

1) complete oxidation of G6P to CO2

2) resynthesis of G6P and ribulose-5-P.

Higher requirement for ribose-5-P than NADPH

G6P is converted to fructose-6-P and glyceraldehyde-3-P by glycolytic pathway

Pentose Phosphate Pathway has …… stages
2

 

Pentose Phosphate Pathway Stage I

 

Decarboxylation of hexose to pentose yielding NADPH.

IRREVERSIBLE

Pentose Phosphate
Pathway
Stage II

 

  • Interconversions of pentose-Ps leads to glycolytic intermediates.
  • (REVERSIBLE)

Glucose-6-Phosphate Dehydrogenase

 

Catalyzes the first step in the pentose phosphate pathway
Rate limiting step
Uses NADP as a cofactor (reaction generates NADPH)
Highly regulated by NADPH/NADP ratio

NADPH/NADP ratio = high
inhibits G6PD
NADPH/NADP ratio= low
activates G6PD

 

NADPH

 Primarily uses high energy electrons for biosynthesis:

        –Fatty Acids

         –Steroids

 

NADH

 

Uses high energy electrons to make energy (ATP via oxidative phosphorylation)

Functions of NADPH

 

Provide high energy electrons for reductive

 biosynthesis

Used as a cofactor by enzymes that deal with

 reactive oxygen species (ROS)

 

These functions cannot be replaced by NADH

Reactive Oxygen Species

 

I.) Superoxide Anion

II.) Hydrogen Peroxide

III.) Hydroxyl Radical

Superoxide Anion

 

O2

 

——produced biologically by a variety of reactions most notably by “leaky”mitochondrial electron transfer. Electrons can be Transferred from the reduced form of Coenzyme Q to oxygen, thus generating superoxide.

Hydrogen Peroxide

 

H2O2

produced by oxidase enzymes.  Very toxic organic peroxides can be formed from 2e reduction of O2 in compounds containing double bonds (unsaturated fatty acids).

Hydroxyl Radical

OH-

 

produced from a metal catalyzed reaction of superoxide and hydrogen peroxide. Very reactive species that can take part

in free radical chain reactions.

 

Glutathione: A Multifunctional Peptide

  •  
  • Major cellular reductant and suflhydryl buffer
  • conjugated to drugs to make them more soluble
  • amino acid transport across membranes
  • disulfide interchanges in proteins

Cellular Defense Against Oxidative Stress

 

I.Superoxide Dismutase (SOD)-detoxifies superoxide
II. Catalase-heme containing peroxidase that detoxified H2O2
III. There are no known enzymatic systems that deal directly with hydroxyl radicals.  Cells rely on the above two reactions to remove precursors to ROS>

Cu-ZnSOD (cytoplasmic enzyme)

 

enzyme deficiency leads to

severe progressive neurodegenerative disorder: Lateral Sclerosis (ALS) or Lou Gherig’s Disease

Cytochrome P-450 System

 

Liver enzymes detoxify many nasty compounds:

-Drugs

-Steroids

-Alcohols

These enzymes require NADPH as a cofactor.

Lack of G6PD results in

 

  • loss of NADPH production,
  • loss of Glutathione antioxidant system
  • increased oxidative stress,
  • Membrane damage and red blood cell lysis.

X-linked disease

 

is the most common disease causing enzymatic defect in humans (200 million people world wide)

 

Hemolytic anemia can be precipitated by:

  • oxidant drugs (e.g., primaquine)
  • diet (fava beans)
  • infection (induction of NADPH Oxidase).

G6PD Mutations

  • Slightly decreased life span (complications from hemolysis).
Many mutations alter G6PD function.
Many alter the Km and Vmax of the enzyme
Some mutations confer resistance to flaciparum malaria

Drugs that have effect on G6PD

  • Antibiotics
e.g., sulfamethoxazole
  • Antimalarials
e.g. primaquine, chloroquine
  • Antipyretics
e.g. acetanilide

Drugs that has no effect on G6PD
aspirin or acetaminophen
Glucuronic Acid
conjugated to endogenous and exogenous compounds producing a strongly acidic compound that is more water soluble at physiological pH than its precursor

Glucuronic Acid is 

Important in:

 

Drug detoxification
Steroid excretion
Bilirubin metabolism