CLASS: FUNDAMENTALS 1 11:00-12:00
DATE: 8/27/10
DR. PRITCHARD
PENTOSE PHOSPHATE PATHWAY
Scribe: COTY CANTRELL
Proof: ABBY NORTHCUTT
Page 1 of 4
I. PENTOSE PHOSPHATE PATHWAY [S1]:
a. All other pathways thus far begin with a set of molecules at the start, and a set of products at the end (linear
pathway).
b. This pathway is unique, because the product is dependant entirely upon what the cell needs at a given time
c. PPP can also cooperate with glycolysis.
II. PPP OVERVIEW [S2]
a. The most important point to know is that the PPP yields NADPH.
i. NADPH involved in biosynthesis of many types of molecules, including removal of oxidative metabolites.
b. The first three reactions of PPP are oxidative, and are concerned with the interconversion of sugar molecules.
c. High levels of PPP enzymes are found in cytoplasm of liver and adipose cells.
i. Essentially absent in muscle because starting material, glucose-6-phosphate (G6P), is used in ATP
production - glycolysis.
III. NADPH [S3]
a. The difference between NADPH and NADH is the presence (or absence) of the highlighted phosphate group.
i. Note bottom components, adenosine nucleotide (adenine, ribose), and top components of ribose and
nicotinamide.
IV. NADPH [S4]
a. Nicotinamide (highlighted in blue) is derived from niacin (Vitamin B3).
i. The difference between the two is that nicotinamide has an amide functional group instead of a hydroxyl
unit.
b. Again, this molecule is especially important in the removal of oxidative metabolites such as peroxide and
superoxide from our cells.
c. In order to make the NADPH molecule, a source of niacin is necessary.
V. PELLEGRA [S5]
a. Pellegra is an example of a dietary deficiency, and is caused by a niacin deficiency.
i. High corn diets have low amounts of niacin and tryptophan, which can be broken down into niacin.
ii. Native Americans avoided pellagra because they soaked corn with alkaline solution of lime and/or wood
ashes prior to grinding it. This allowed the release of enzyme-bound niacin (niacin in corn is protein coated
with zyne protein).
b. Characterized by the “Three Ds”
i. Dermatitis, Diarrhea, Dementia
c. There were 200,000 cases of pellagra in the U.S. in 1930, almost entirely concentrated in the Southeast.
VI. PELLEGRA (cont.) [S6]
a. Long thought to be infectious disease, until Dr. Goldberger demonstrated pellagra is a result of dietary
deficiencies.
b. (Long story about Dr. Goldberger’s experiments)
c. Niacin in dry yeast cured Pellegra in dogs and humans
VII. NADPH [S7]
a. Here’s NADPH again.
VIII. NADPH [S8]
a. A large number is indicative of high concentrations of numerator.
i. Enzymes that are moving in an oxidative direction utilize NAD+/NADH cofactor pair (such as the liver).
ii. Typically more NAD present
b. A small number (i.e. less than one) is indicative of high concentrations of numerator.
i. Enzymes that are moving in a reductive direction utilize NADP+/NADPH cofactor pair.
ii. Typically more NADPH present
IX. OXIDATIVE REACTIONS OF THE PPP [S9]
a. Step 1: Start with G6P, just like glycolysis, but here you have oxidation [via G6P Dehydrogenase enzyme] to
make NADPH and 6-phospho-glucono-δ-lactone (a cyclic ester).
b. Step 2: 6-phospho-glucono-δ-lactone can cleave spontaneously or with 6-Phosphogluconolactonase enzyme
to produce 6-Phosphogluconate.
c. Step 3: This product is subsequently oxidized [via Phosphogluconate Dehydrogenase enzyme] to make
NADPH and ribulose 5-phosphate and CO2.
d. Note that these steps form 2 NADPH molecules (Remember: most important product of PPP).
X. EPIMERASE AND ISOMERASE REACTIONS OF THE PPP [S10]
a. Ribulose 5-phosphate (middle molecule) can be interconverted.
b. Left Reaction: Phosphopentose isomerase catalyzes the conversion of ribulose 5-phosphate to ribose 5phosphate.
CLASS: FUNDAMENTALS 1 11:00-12:00
Scribe: COTY CANTRELL
DATE: 8/27/10
Proof: ABBY NORTHCUTT
DR. PRITCHARD
PENTOSE PHOSPHATE PATHWAY
Page 2 of 4
i. Ribose 5-phosphate needed in the synthesis of RNA and DNA
ii. Isomerase enzymes interconvert a ketose sugar to an aldose sugar.
c. Right Reaction: Phosphopentose epimerase catalyzes the conversion of the hydroxyl group to the opposite
side of Carbon-3.
XI. TRANSKETOLASE [S11]
a. Transketolase catalyzes reaction of Xu6P and R5P (two 5-Carbon sugars) into GAP and Sed7P (3-Carbon
and 7-Carbon sugars, respectively)
b. Sed7P is a starting material for a variety of biosynthetic pathways
XII. TRANSALDOLASE [S12]
a. Transaldolase catalyzes reaction of GAP and Sed7P to Ery4P and F6P (4-Carbon and 6-Carbon sugars,
respectively)
XIII. TRANSKETOLASE [S13]
a. “Important reaction because if you are unable to do it, you will have serious problems”
XIV.
FIRST OXIDATION (G6P) [S14]
a. SKIPPED
XV.
SECOND OXIDATION (6PGLUCONATE) [S15]
a. SKIPPED
XVI.
EPIMERASE AND ISOMERASE OF R5P [S16]
a. Notice that the epimerase and isomerase reactions occur via an Enediol intermediate (note the double bond
placement).
b. Enzymes aid formation of double bond in a specific manner in order to facilitate Xu5P or R5P product.
XVII. TRANSKETOLASE [S17]
a. Transketolases always transfer 2-Carbon unit (highlighted in yellow) from ketose to aldose.
b. The net effect of this reaction forms a new aldose, and a much larger ketose.
XVIII. TRANSKETOLASE (repeated) [S18]
a. Again, always a 2-Carbon unit from ketose to aldose.
XIX.
THIAMINE PYROPHOSPHATE [S19]
a. Transketolase reactions absolutely require another cofactor, Vitamin B1 (thiamine pyrophosphate or TPP).
b. Proton of 5-membered ring has an acidic proton, considered “acidic” because it easily comes off.
XX.
BERI-BERI [20]
a. Beri-Beri is also a dietary deficiency, but is a Vitamin B1 (thiamin) deficiency.
b. Again thought to be infectious disease, until Dr. Eijkman noticed a change in animal diet affected the
presence of disease.
i. Husked rice  beri-beri; wild fed  cured beri-beri
c. Rice germ was removed by polisher to preserve it, but husks have all the thiamin content of the rice.
d. Etymology of Vitamin: Vitamine (vital amine) shortened to vitamin after Vitamins A, C, and E discovered (sans
amine group).
XXI.
DIAGRAM OF TRANSKETOLASE MECHANISM [S21]
i. 2-Carbon unit of ketose (Xu5P) binds to acidic carbon of cofactor TPP and allows release of GAP.
ii. Now another aldehyde (R5P) can be linked to 2-Carbon unit to produce longer ketose (Sed7P).
iii. Final separation from TPP forms 7-Carbon free ketose, Sed7P.
XXII. TRANSALDOLASE[S22]
a. Transaldolase moves a 3-Carbon unit, again from a ketose to an aldose.
i. In this case, you have a mechanism of creating F6P and Ery4P.
b. Reaction may proceed in either direction depending upon what cell needs.
XXIII. DIAGRAM OF TRANSALDOLASE MECHANISM [S23]
a. SKIPPED BUT NOTE THAT ALDOLASES DO NOT USE TPP
XXIV. DIAGRAM OF FIRST FOUR REACTIONS [S24]
a. Reactions proceed based entirely on what cell needs at a given time.
b. For example, if a cell is getting ready to divide, the first four reactions of PPP will predominate in order to
generate R5P (for RNA/DNA) and NADPH.
i. Products come from 1st four reactions of PPP
c. Take home message is that you do not necessarily have to proceed to transaldolase and transketolase
reaction pathways if all the cell needs is NADPH and R5P.
XXV. DIAGRAM OF GLYCOLYSIS/PPP [S25]
a. In this case, the cell is looking to synthesize a large amount of R5P.
b. The steps of the top left intermediates are the first phases of glycolysis.
c. Spend a few minutes on these two diagrams, but note that enzymes from both glycolysis and the PPP work
together to make products as needed.
CLASS: FUNDAMENTALS 1 11:00-12:00
Scribe: COTY CANTRELL
DATE: 8/27/10
Proof: ABBY NORTHCUTT
DR. PRITCHARD
PENTOSE PHOSPHATE PATHWAY
Page 3 of 4
i. TK = transketolase
ii. TA = transaldolase
XXVI. DIAGRAM OF GLYCOLYSIS/PPP [S26]
a. In this case, the cell is looking to synthesize a large amount of NADPH (your cell is making steroids, for
example)
b. G6P is oxidized to R5P, and subsequently converted back to G6P.
c. Note that the starting material and end product of this reaction is the same. This allows the cell to make a
massive amount of NADPH.
XXVII. REACTION SUMMATION [S27]
a. The summation of chemical equations is shown in order to illustrate that one molecule of G6P produces 12
molecules of NADPH
XXVIII. DIAGRAM OF G6P  CO2 AND ATP REACTION SERIES [S28]
a. *Did not cover, but discussed the point of the slide is to illustrate a reaction may proceed in different ways
depending on the needs of the cell
XXIX. GLUTATHIONE [S29]
a. In normal metabolism, cell creates oxidative metabolites such as hydrogen peroxide.
b. This happens in a RBC, for example, and the oxidative metabolites can oxidize iron of hemoglobin or damage
cell membranes.
c. Key molecule for destroying oxidative metabolites is Glutathione, and requires NADPH for mechanism to
proceed.
i. Molecule consists of a chain of glycine, cysteine, glutamic acid residues
ii. Linked via gamma carboxyl group (NOT typical peptide linkage - alpha)
iii. Active site of glutathione is the sulfur of cysteine group
iv. Reduced (G-SH) is active form and is catalyzed by Glutathione Peroxidase
v. NADPH donates hydrogen to reduce Glutathione
1. Glutathione Reductase re-reduces glutathione & uses up an NADPH
vi. No NADPH = No regeneration of Glutathione
1. Oxygen metabolites will build up & harm cell
XXX. GLUTATHIONE PEROXIDASE [S30]
a. Unique molecule, in that it incorporates a rare amino acid into sequence, selenocysteine (Cysteine bound to
Selenium).
b. This amino acid is incorporated during translation, and does not occur as a post-translational modification.
c. The stem-loop (2˚ structure) of the mRNA causes the stop-codon UGA to code for Se-Cys instead.
XXXI. G6P DEHYDROGENASE DEFICIENCY [S31]
a. Carries out the first oxidation in the PPP pathway.
b. Mutants typically have varying levels of enzyme activity, depending upon extent of variation.
c. The disease results in acute hemolytic anemia due to a build up of oxidative metabolites.
i. NADPH concentration not high enough to maintain adequate Glutathione levels.
ii. Iron-bound hemoglobin oxidized and non-functional, as well as lysing of cells from damage to cell
membrane.
d. Lacking the 1st enzyme in PPP means that you cannot make enough NADPH to regenerate glutathione which
is responsible for getting rid of the oxygen metabolites
XXXII. G6P DEHYDROGENASE DEFICIENCY (cont) [S32]
a. Amount of variation is defined by amount of amino acid residue mutation.
b. Gene is found on X-chromsome so males are primarily affected (females will be affected if gene is found on
both X-chromosomes).
c. Enzyme defects like this in population are often protective in some way.
XXXIII. G6P DEHYDROGENASE DEFICIENCY [S33]
a. Female carriers are resistant to malaria, as increased levels of oxidative metabolites in RBC are protective
against parasites.
b. Mediterranean types, although a typically a more serious variant, is often asymptomatic until an episode is
triggered (see S35).
XXXIV. IMAGE OF PARASITISED RBC [S34]
XXXV. TRIGGERS OF ACUTE REACTIONS [S35]
a. Triggers may include pharmaceuticals, as well as bacterial and viral infections.
XXXVI. FAVISM [S36]
a. Fava beans contain highly oxidative glycosides, resulting in a large intracellular concentration of oxidative
metabolites.
b. Oxidants responsible are two polyhydroxypyrimidine ß-glucosides, divicine, and isouramil.
CLASS: FUNDAMENTALS 1 11:00-12:00
DATE: 8/27/10
DR. PRITCHARD
PENTOSE PHOSPHATE PATHWAY
XXXVII. PPP SONG [S37]
XXXVIII.
PPP SONG (cont) [S38]
XXXIX.
WEBSITE OF BIOCHEMISTS’ SONGBOOK [S39]
a. http://www.csulb.edu/~cohlberg/songbook.html
[End 41:17 mins]
Scribe: COTY CANTRELL
Proof: ABBY NORTHCUTT
Page 4 of 4