Pentose Phosphate Pathway

Dr. Jones LLU

Three purposes of pentose phosphate pathway

1.Synthesis of ____ - source of reducing power in synthetic reactions

2.Synthesis of _____ - utilized in DNA and RNA

3.Mechanism for conversion of ____ to triose and hexose intermediates of glycolysis

1. NADPH

2. ribose 5-P

3. pentose sugars

2 phases of pentose phosphate pathway

oxidative phase w/ 3 irreversible reactions, nonoxidative phase with set of reversible sugar inteconversions

Oxidative phase of pentose phosphate pathway

glucose 6-P → ribulose 5-P + CO2 + NADPH

Pentose phosphate pathway oxidative phase important in liver, adipose, and mammary glands for NADPH-dependent ____ synthesis, Important in RBCs for the NADPH-dependent ____ of glutathione

fatty acid, reduction

Nonoxidative phase

•Ribulose 5-P is converted to ____ for use in nucleotide synthesis

•Glycolytic intermediates G3P and fructose 6-P can form ___ without oxidative reactions

Occurs in all cell types synthesizing nucleotides and nucleic acids

ribose 5-P, ribose 5-P

Nonoxidative reactions are all…

reversible

Oxidative phase irreversible reaction: glucose 6-phosphate dehydrogenase (G6PD) drives the following

glucose 6-P + NADP+ → 6-phosphogluconolactose + NADPH + H+

Glucose 6-Phosphate Dehydrogenase (G6PD)

•Catalyzes ____ of the pentose phosphate pathway

•Committed, rate-limiting, and ____ step!

•Regulation:  G6PD is inhibited by NADPH, induced by ____

•Normally NADPH/NADP⁺ is high enough to inhibit pathway

•As need for NADPH ↑, the ratio ↓ and pathway flux ↑ (absorptive state)

• first step

• regulated

• insulin

G6PD is the only ___ step

rate limiting

G6PD Deficiency (most common genetic variant)

•Most common inborn error of metabolism - > 400 million people affected worldwide

•Highest prevalence in Middle East, tropical Africa, & Asia

•____ recessive mutation

x-linked

Primary clinical manifestation of G6PD deficiency is ____: anemia due to hemolysis/breakdown of red blood cells

Hemolytic Anemia

Pathophysiology of G6PD deficiency:

•Not enough ____ to maintain glutathione in reduced (active) form

•Glutathione = ____ for detoxification of free radicals

•Inability to reduce glutathione leads to free radical damage and red cell death

•Occurs in all cells, but most severe in red blood cells (other cells make NADPH by alternate pathway)

•Triggered by _____: infection, certain foods (fava beans), oxidant medications

• NADPH

• antioxidant

• oxidative stress

What is the most important antioxidant in our cells?

Glutathione

Glutathione

•____ - glutamate-cysteine-glycine (three important amino acids

•Exists in ____ (GSH) and ____ (GSSG) states

•In the reduced state (GSH), the thiol group of cysteinyl residue is a source of one reducing equivalent, used to reduce (squelch) ____ (e.g. H₂O₂)

•Two GSH molecules generate a _____ (GSSG)

•GSH is regenerated by ____

•Ratio of reduced to oxidized ____ within cells is a measure of cellular oxidative stress

• tripeptide

• reduced, oxidized

• free radicals

• glutathione disulfide

• NADPH

• glutathione

NADPH reduces…

GSH

Glucose 6-phosphate dehydrogenase deficiency impairs the ability of an erythrocyte to form NADPH, resulting in…

hemolysis