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Pentose Phosphate Pathway - Coggle Diagram
Pentose Phosphate Pathway
Complete oxidation of glucose to CO\(_2\)
Neither consumes nor produces any ATP
Produces NADPH in first stage
Reaction occurs in the cytosol (~1.5% found in ER)
Oxidative stage
Non-reversible
Generates NADPH from G-6-P
Reaction
Oxidative carboxylation of G-6-P
G-6-P + 2xNADP\(^+\) + H\(_2\)O \(\rightarrow\) ribulose-5-phosphate + CO\(_2\) + 2xNADPH + 2H\(^+\)
G-6-P converted to 6-Phosphogluconolactone
6-Phosphogluconolactone converted to 6-Phosphogluconate
Lactonase
Splits carbon ring open
Reaction is spontaneous -
lactonase
increases rate
H\(_2\)O
H\(^+\)
6-phosphogluconate converted to ribulose-5-phosphate
6-phosphogluconate dehydrogenase
NADP\(^+\)
NADPH + H\(^+\)
Ribulose-5-phosphate
G-6-P dehydrogenase
Important rate controlling enzyme
NADP\(^+\)
NADPH + H\(^+\)
Electron acceptor
Regulation
Intracellular ratio of NADPH/NADP\(^+\)
NADPH is an allosteric inhibitor of
G-6-P dehydrogenase
High levels of NADPH - enzyme switched off
Low levels - enzyme active
NADP\(^+\) is co-factor for
G-6-P dehydrogenase
High levels of NADP\(^+\) - lots of enzyme activity
Low levels - reduced enzyme activity
Expressed in all cells of the body
All tissues may experience oxidative stress
In most tissues except skeletal muscle 80-90% glucose fed through glycolytic pathway
Remaining 10-20% through PPP
Tissues rich in PPP enzymes
Tissues involved in fatty acid synthesis + steroid biosynthesis
Liver
Adipose tissue
Adrenal cortex
Testes
Mammary glands (lactating)
Erythrocytes contain large amounts of NADPH to maintain reduced glutathione
PPP is only way to produce NAPH in erythrocytes
Skeletal muscle tissue has very low levels of PPP enzymes
Commits most of its glucose to glycolysis
Phase 2 (Non-oxidative stage)
Ribulose-5-phosphate converted to
Ribose-5-phosphate for nucleotide biosynthesis
Glycolytic intermediates
6 ribulose-5-phosphate can produce 5 glucose-6-phosphate to be fed back into the start of PPP
Reversible
Different sub-pathways used in different needs/conditions
Ribulose-5-phosphate isomerase pathway
Produces 2 x ribose-5-phosphate from 6 ribulose-5-phosphate
Structure rearranged
Ribulose-5-phosphate 3-epimerase
Rearranges structure producing epimers
Produces 4 x xyulose-5-phosphate
Transketolase
Intercalates ribose-5-phosphate + xyulose-5-phosphate to produce sedaheptulose-7-phosphate (rare molecule) and glyceraldehyde-3-phosphate
Requires thiamine pyrophosphate co-factor
Deficiency is Beri Beri syndrome
Wernicke-Korsakoff syndrome from chronic alcoholic
Gut of pateint altered due to excess alcohol- thiamine cannot be absorbed
Storage in liver dystfunction
Transaldolase
Intercalates sedaheptulose-7-phosphate + glyceraldehyde-3-phosphate producing
erythose-4-phosphate
Transketolase with xylulose-5-phosphate produces
Glyceraldehyde-3-phosphate
Combine 2 molecules to form glucose-6-phosphate
fructose-6-phosphate
fructose-6-phosphate
Phosphoglucose isomerase converts to
Glucose-6-phosphate
Back into start of PPP
Substrates of PPP do not have a clearly defined course
Need for NADPH + ribose-5-phosphate are balanced
Mainly oxidative pathway used
Nucleic acid synthesis from ribose-5-phosphate
More NADPH than ribose-5-phosphate needed
Whole pathway used
Recycle the ribulose-5-phosphate into glucose-6-phosphate back into the start of the pathway
Cell mainly needs ribose-5-phosphate
Non-oxidative part is used in reverse
e.g. rapidly dividing
First part of pathway is not used
Inhibited by lack of need for NADPH
Glucose-6-phosphate dehydrogenase deficinecy
Most common enzyme abnormality
400 million people worldwide
Most prevalent in Middle East , tropical Africa + Asia + parts of Meditarranean
Similar distribution to malaria
Malaria protection hypothesis
Malaria needs G6PD to survive in erythrocytes
People without survive longer
Deficiency is selected for
X-linked disease (Xq28)
Haemolytic anaemia
Classes based on severity of symptoms
I - Very severe
II - Severe (episodic)
III - Moderate (episodic)
IV - None
All other cells use malate dehydrogenase to produce NADPH but erythrocytes cannot - hence disease manifests as haemolytic anaemia
Severe oxidative stress
All NADPH is consumed
Jaundice due to increased breakdown of Hb
~186 mutations in G6PD gene
Single base changes leading to amino acid substitutions
Glutathione system
Cells need protection from hydrogen peroxide (produced as by-product from many cell reactions)
Converted to water by glutathione peroxidase
2 x reduced glutathione (G-SH) needed
Contains free sulfhydrl group
2 x hydrogen donated to hydrogen peroxide
Oxidised glutathione produced
Useless form
Glutathione reductase reproduces reduced from
Needs NADPH
Hydroxy group destroys plasma membrane
Cleaves C-C bonds in fatty acids
Formation of Heinz bodies
Protein denaturation via oxygenation of sulfhydryl groups
Removed by spleen
Episodic manifestations
Erythrocyte loss balanced by production (Normal)
When loss increases by precipitating factor episodic anaemia occurs
Precipitating factors
Oxidant drugs
Antibiotics
Antimalarials
Antipyretics
Favism
Broad beans contain high levels of vicine, divicine, convicine + isouramil
Oxidants
Infection
Most common
Respiratory burst from M\(\phi\)