Pentose phosphate pathway Flashcards
what is the pentose phosphate pathway
- completely different pathway of glucose oxidation
- aka the hexose monophosephate shunt
- oxidation WITHOUT ATP production
purpose of the pentose phosphate pathway
- supplies ribose-5-phosphate for nucelotide and nuceil acid synthesis
- supplies reducing power as NADH for synthesis of fat, cholesterol, steroids etc
- provides route for excess pentose sugar inthe diet into mainstream metabolism
- recycles sugars according to the needs of the cell
two phases of the PPP
oxidative and non-oxidative
why doesnt PPP produce ATP
because the NADPH doesn’t go to the mitochondria and ETC
where does PPP occur
mainly in the cytosol of cells, along with glycolysis
where are PPP enzymes most plentiful
- in tissues with high demand for NADPH for synthesis
- rapidly dividing cells which require ribose-5-phosphate for DNA synthesis
- in the liver, because the main demand is for FA synthesis
quantitatively, what is the main demand of PPP
FA synthesis
PPP in skeletal muscle
very little activity
but because PPP produces ribose-5-phosphate, all tissues are likely to have some activity
why do mature erythrocytes need the PPP
they require NADH to maintain the cell membrane integrity
- maintains the reduced environment to stop bursting
which part of PPP is irreversible and produces ribose-5-phosphate and NADPH
oxidative
steps of the oxidative PPP
- G6P converted to 6-phosphgluconate
- NADP+ reduced to NAPDH
enzyme: glucose-6-dehydrogenase - 6-phosphogluconate dehydrogenase reduces NADP+ and generates beta-keto-acid
- beta-keto-acid decarboxylated to keto-pentose-ribulose-5-phosphate
- isomerase converts keto-pentose-ribulose-5-phosphate into aldose isomer: riose-5-phosphate
what controls the oxidate part of PPP
rate limiting step: oxidation of G6P to 6-phosphogluconolactone, by enzyme glucose-6-dehydrogenase
rate of reaction is tightly coupled to [NAD+] which governs the allocation of G6P to PPP instead of glycolysis
non oxidative part of PPP
- Interconverts sugars according to needs of cells
- involves transaldose and transketolases
what do transaldose and transketolase do in the non-oxidative part of PPP
detach C3 and C2 respectively from ketose sugar phosphate, and transfer them other aldose sugars
what is the thiamin (B1) pyrophosphate-dependent enzyme
transketolase (like in the link reaction)
when do tissues demand high NADPH
during fat synthesis
- production of NADPH for fat synthesis also results in increased ribose-5-phosphate
- there might be more R5P than cell needs for nucleotide synthesis
when do tissues demand high R5P
rapidly dividing cells that arent synthesizing fat, have high requirement for R5P but not NADPH
how do requirements for NADPH and R5P alter
vary with different tissue demands
the demand for R5P and NADPH can be equal, or weighted to one more than the other
production is controlled by the non-oxidatve part of the pathway
what controls balance of NADPH and R5P production
non-oxidative part of PPP
Oxidative balance equation
G6P + 2NADP+ + H2O –> R5P + 2NADPH + 2H+ + CO2
when is the non-oxidative part of PPP not needed
when the oxidative part is balanced
When does conversion of R5P to X5P occur
when the liver needs 2NADPH but does not need the R5P of the balance equation
- phosphophentose isomerase and epimerase
X5P
xylulose 5 phosphate
what else does R5P get converted to when in excess
R5P to glyceraldehyde3P and F6P
- these can enter glycolysis or gluconeogenesis
- F6P can also be converted to G6P and reenter PPP
occurs by 3 reactions using transketolase, transaldolase and transketolase again
conversion of surplus R5P into G6P: when and how
if non dividing cell requires more NADPH than R5P
the non-oxidative part recycles excess into G6P
6 R5P -> 5 G6P + Pi
conversion of R5P into glyceraldehyde-3-phosphate: why
G3P can then be converted to G6P by gluconeogenesis reactions
6 C5 sugars are converted to
5 x G6P
(3 R5P and 3 XYP
conversion of G6P into R5P without NADPH generation : summary
if a cell needs R5B for nuceotide synthesis but has little demand for NADPH:
G6P + ATP -> 6R5P + ADP + Pi
- where R5P is required and NADH isnt
- oxidative part of PPP doesn’t operate
- glycolytic intermediates are converted to R5P by transketolase and transaldolase enzymes
steps of conversion of G6P into R5P without NADPH generation
- G6P is converted by glycolytic pathway partly in F6P an partly into glyceraldehyde3P
= C3 and C6 products - reversal of the these steps produces X5P which is isomerised to R5P
why is the PPP important for erythrocyte
- mature erythrocytes do not divide
- no need for R5P for nuclei synthesis or fat synthesis bc they derive energy from glycolysis
BUT they need a supply of NADPH to protect cell membrane from oxidative damage
Protective effect of NADPH on erythrocytes
- RBC membrane is subject to attack by H2O2
- H2O2 needs to be detoxified
- 2 reduced GSH attack H2O2 to make water and the GSH become oxidised to GSSG
- GSSG is useless so FAD re-reduces to farm GSH again
- NADPH is needed to activate the GSSG to GSH
Main function of glutathione
to maintain reducing environemnt in cells by virtue of its -SH group (thiol)
AHA GSH
why are RBC susceptible to oxidative damage
- high O2 content in cell gives rise to harmfel ree radicals or ROS
- RBC depend on GSH for integrity
- GSH reduces ferrihaemoglobin to ferrous form
- GHS destroys H2O2
- GSH regenerates reduction environemnt using NADPH
why does RBC depend on GSH
- GSH reduces ferrihaemoglobin to ferrous form
- GHS destroys H2O2
- GSH regenerates reduction environemnt using NADPH
therefore continuous supply of NADPH is also key
GSH
glutathione
what is the only way of generating NADPH and GSH inthe cell
PPP and hence vital for RBC
G6P dehydrogenase deficiency
most common human enzyme disorder
- X-linked hereditary disorder so most asymptopic
- symptopic patients usally male
- more than 400mil worldwide are G6PD deficient, mostly in Africa, middle East and south Asia
what happens to people with G6PD
they can be completely OK until ertythrocyte is challenged with oxidation
= haemolytic anaemia
triggers for haemolytics anaemia
- favism
- infection
- oxidant drugs
favism
ingestion of fava beans
- some forms of G6PD, particulary mediterraneon varient, are particulary susceptible to favism
- fava beans contain alkaloids such as vicine which are potent oxidants
infection triggering haemolytic anaemia
inflammatory response to infection can lead to generationof oxidatns such as fre radicals, which enter E and cause haemolysis
oxidant drugs triggering haemolytic anaemia
antimalaria drugs; chloroquine can be harmful
- indivuduals should be tested for G6PD before being prescribed these
- sulphonamides, sulfa antiobiotics and analgesics should also be avoided
sidelight of G6PD
selective advantage in areas where lethal type of malaria is endemic
possible reasons:
- parasite had requirement for products of PPP
- AND/OR extra stress by parasite causes the deficient RBC host to lyase before parasite completes development (doesnt live usual 120 days)
similar to sickcell - potentially lethal disease that provides survival advantage against an even more lethal disease
