Lecture 22- Pentose Phosphate Pathway

State the purpose of the pentose phosphate pathway by describing the two most significant products for the cell.

The pentose phosphate pathway (PPP), which converts glucose-6-phosphate to ribose-5-phosphate, is an oxidative pathway that occurs in all cells (cytoplasm). As much as 30% of glucose in the liver is catabolized by the pentose phosphate pathway

Purposes of PPP

• Alternative way to oxidize glucose

• Produces pentoses for nucleotide synthesis

• Produces NADPH

Identify the two stages of the pentose phosphate pathway and list the key products of each stage

The pentose phosphate pathway (PPP) can be divided into two phases: a series ofoxidative reactions followed by a series of reversible interconversion reactions.

• The oxidative phase generates NADPH and pentose phosphates.

• The nonoxidative phase converts the pentose phosphates that are in excess of cell requirements back to glycolytic intermediates

• fructose 6-phosphate

• glucose 6-phosphate

• glyceraldehyde 3-phosphate

The first phase is the oxidative generation of 2 molecules of NADPH, and the second phase is the nonoxidative interconversion of three-, four-, five-, six-, and seven-carbon sugars

Unlike glycolysis, the PPP generates ___ rather than NADH

NADPH

The oxidative phase of the pentose phosphate pathway produces ____ and two of the pathway's three steps generate 1 ____ each

pentose phosphate(ribulose 5-phosphate)

NADPH

The nonoxidative phase recycles pentose phosphates to two molecules of ____ and one molecule of _____

fructose 6-phosphate

glyceraldehyde 3-phosphate

PPP and glycolysis are reversibly linked by

transketolase and transaldolase

transketolase and transaldolase

Transketolase (transfer 2-carbon segment) and transaldolase (transfer 3-carbon segment)catalyze reversible reactions that transform three five-carbon sugars into two six-carbon sugars (2 molecules of fructose-6-phosphate) and one three-carbon sugar (glyceraldehyde-3-phosphate

For the rate determining step of the pentose phosphate pathway, name the products and reactants (including cofactors & coenzymes), name the enzyme that catalyze the step, classify the enzymatic step into the 6 enzyme classes, and determine if the step is reversible or irreversible.

Glucose-6-phosphate dehydrogenase (G6PD)

reactants:Glucose-6-phosphate

products:6-phosphoglucono-δ-lactone

cofactor: NADP⁺ → NADPH + H⁺

Oxidoreductase

irreversible

Outline the steps of both the oxidative and nonoxidative phases of the pentose phosphate pathway and indicate which steps are irreversible and reversible

Oxidative Phase (Irreversible)

Purpose: Generate NADPH (for biosynthesis and antioxidant defense)

Produce ribulose-5-phosphate (Ru5P) for nucleotide synthesis

Nonoxidative Phase (Reversible)

Purpose: Rearrange 5-carbon sugars to form glycolytic intermediates (fructose-6-phosphate and glyceraldehyde-3-phosphate)

Supply ribose-5-phosphate for nucleotide synthesis or draw intermediates back into glycolysis/gluconeogenesis

know how to draw out steps

Explain how the pentose phosphate pathway is coordinated with glycolysis and gluconeogenesis by describing the regulation of the oxidative phase of the pentose phosphate pathway

PPP is regulated by [NADP+ ]

The fate of glucose 6-phosphate is controlled by cytoplasmic [NADP+]

Low levels of NADP+ limit dehydrogenation of glucose 6-phosphate because it is needed as the electron acceptor. This ensures NADPH is not generated unless needed for reductive biosyntheses or protection against oxidative stress.

Mode 1

Using glycolysis & PPP for nucleotide synthesis

Bypassing the oxidative phase of the pentose phosphate pathway, mode 1 starts with fructose 6-phosphate & glyceraldehyde 3-phosphate from glycolysis and then synthesizes ribose 5-phosphate using the reversible reactions

Mode 2

Using PPP for nucleotide synthesis and NADPH production

When the needs for NADPH & ribose 5-phosphate are balanced, two molecules ofNADPH are produced and ribulose 5-phosphate is converted into ribose 5-phosphate

Mode 3

Using PPP for NADPH synthesis

When the cell needs NADPH (reducing power or protection against reactive oxygenspecies), glucose 6-phosphate is regenerated to start another oxidative phase.

1. Oxidative phase plus first step of nonoxidative phase

2. Transketolase and transaldolase catalyzes reversible reactions

3. Gluconeogenesis from both fructose 6-phosphate &glyceraldehyde 3-phosphate produce glucose 6-phosphate

Mode 4

Using PPP for NAPDH and ATP

When both NADPH and ATP are required, NADPH will be produced in the PPP's oxidative phase and then ribulose 5-phosphate is converted to glycolytic intermediates for cellular respiration

Explain how glucose 6-phosphate dehydrogenase and glutathione play important roles in protection against reactive oxygen species

Reduced glutathione (GSH) is a tripeptide with a free sulfhydryl group that combats oxidative stress by reducingROS to harmless forms.

• NADPH generated by glucose6-phosphate dehydrogenase maintains the appropriate levels of reduced glutathione required to combat oxidative stress, and it ensures the proper reducing environment in the cell.

Glutathione is an important...

antioxidant

Reduced glutathione (GSH) is a tripeptide with a free sulfhydryl group that combats oxidative stress by reducing ROS to harmless forms. Oxidized glutathione (GSSG),produced as a biproduct, must be reduced to regenerate GSH

Reduced glutathione is regenerated using...

NADPH

Oxidized glutathione is reduced to reduced glutathione using a NADPH-dependent enzyme, glutathione reductase. Reducing power is supplied by the NADPH generated by glucose 6-phosphate dehydrogenase in the pentose phosphate pathway

symptom of glucose 6-phosphatase deficiency

The biggest symptom is hemolytic anemia from lack of NADPH production

Describe the outcomes of glucose 6-phosphatase deficiency by explaining how it affects health and disease

Lack of NADPH in G6PDH deficiency results in increased ROS and oxidative damage

Since NADPH is critical in protecting against oxidative stress through glutathione and glutathione peroxidase, patients with G6PDH deficiency suffer severe oxidative stress.

how do fava beans play into glucose 6-phosphatase deficiency?

Fava beans is a trigger for hemolysis in patients with G6PDH deficiency

Vicine is a pyrimidine glycoside of fava beans. People deficient in glucose 6-phosphatede hydrogenase suffer hemolysis from eating fava beans

what is another triggers for hemolysis inpatients with G6PDH deficiency?

infections

Patients with G6PDH deficiency are susceptible to infections because their immunecells (neutrophils and macrophages) cannot produce ROS to effectively kill pathogens.This is because the ROS cascade starts with NADPH oxidase

Drugs that cause oxidative stress are triggers for hemolysis in patients with G6PDH deficiency

If patients have a deficiency of glucose 6-phosphate dehydrogenase, they can develop drug-induced hemolytic anemia from certain drugs because red blood cells they lack mitochondria and thus rely heavily on NADPH production by the PPP. (Anti-malaria drugs, Sulfa drugs)

what maintains the structure of hemoglobin

Glutathione

Reduced form of glutathione serves as a sulfhydryl buffer that keeps the residues of hemoglobin in the reduced sulfhydryl form. Without adequate levels of reduced glutathione (as in G6PDH deficiency), hemoglobin molecules cross-link with one another to form aggregates called Heinz bodies on cell membranes.

G6PDH deficiency can be protective against...

malaria

The parasites causing malaria require NADPH for growth. Moreover, infection by theparasites induces oxidative stress in infected human cells. Because the PPP iscompromised, the cells and parasite die from oxidative damage.