LECTURE 4 - PENTOSE PHOSPHATE PATHWAY Flashcards
where does most of the fructose in the blood go?
95% in the liver
5% to the muscle
what is the first reaction that happens to fructose in the liver?
the enzyme fructokinase (strictly expressed in the liver) phosphorylates fructose to make fructose-1-phosphate
what makes fructokinase different from hexokinase?
not allosterically inhibited, can process a lot of fructose
what are the two options of the fructose pathway in the liver?
option 1:
fructose converted to GAP, which then joins back to be an intermediate in glycolysis
option 2:
fructose is converted to glycerol-3-phosphate
substrate for fatty acid synthesis
how does the cell choose between option 1 and option 2 for the fructose pathway in the liver?
depends on the needs of the cell
if it needs fats=option 2
if it needs glycolysis=option 1
what happens to fructose when it enters the muscle?
phosphorylated by hexokinase to make fructose-6-phosphate
then PFK to make fructose-1-6-phosphate
then fructose-1-6phosphate aldolase to make DHAP and GAP
this then joins back glycolysis
what are the entry points of fructose (liver and muscle) into glycolysis and what does this mean?
fructose from muscle enters at the F6P step, before the PFK point of control
since it is before the limiting step, this can slow down the process
fructose from the liver enters after the PFK point of control
(could contribute to increased dyslipidemia)
not regulated
what is the glucose vs fructose metabolism in the liver in a fed state?
the glucose in the liver will be used to make glycogen
fructose bypasses the PFK control and is converted to fatty acids, goes through with all of glycolysis
what is the effect of citrate in the fructose liver pathway?
activates fatty acid synthesis
what is the difference in fructose metabolism in non liver vs liver?
fructose non liver:
goes through the cycle, generates energy
fructose in liver:
generates fatty acids
what is the galactose metabolism pathway and where does it happen?
- galactose is converted to galactose-1-phosphate by galactokinase (galactose is NOT a substrate for hexokinase)
- galactose-1-phosphate is converted to UDP-galactose, and the UDP comes from UDP-glucose (already in cells), transferred by galactose-1-phosphate uridylyl transferase
- UDP glucose is regenerated by UDP-galactose-4-epimerase
- UDP glucose is transformed into glucose-1-phosphate
- glucose-1-phosphate is made into G6P by phosphoglucomutase
- G6P is now an intermediate in glycolysis
happens mostly in the liver
where does galactose enter glycolysis?
at the G6P step
before the PFK1 point of control
what is galactosemia?
rare autosomal recessive genetic disorder
inability to process galactose
galactose accumulates and gives liver disease, vomiting, lethargy, mental retardation, cataracts
the treatment is to avoid dairy products and galactose
what are the different types of galactosemias?
type 1: issue with galactose-1-phosphate uridylyl transferase
type 2: issue with galactokinase
type 3: issue with UDP-galactose-4-epimerase
how can a galactosemic mother produce milk?
in the mammary gland inorganic pyrophosphate is converted to 2 inorganic phosphates
this is a highly exergonic reaction, used to invert the epimerase reaction
the reaction is reversed, UDP glucose is made into UDP galactose, and the mother can make galactose and produce milk
where is mannose found?
found on glycolipids
get them from any cell
what is the pathway of mannose?
substrate of hexokinase
mannose is phosphorylated by hexokinase, eventually ends up as fructose-1-6-phosphate, which is an intermediate in glycolysis
where does mannose enter glycolysis?
at the F6P step
what does the pentose phosphate pathway (PPP) produce from glucose-6-phosphate?
makes ribose-5-phosphate
where does the PPP branch off and branches back in in glycolysis?
branches off at G6P
branches back in at F6P and GAP
what is the committing enzyme to the PPP?
glucose-6-phosphate dehydrogenase
what is the output of the PPP?
ribose-5-phosphate (R5P)
NADPH
where is the pathway present?
liver (30% of G6P)
adipose tissue
red blood cells
not present in muscle
what is R5P used for?
used for the synthesis of nucleotides
ATP, GTP, TTP, CTP
what are the differences between NADH and NADPH?
different by a phosphate group, NOT interchangeable, enzymes have a high specificity for either NADH or NADPH
what is the purpose of the PPP?
to make NADPH
in which cells in particular is the PPP activated?
cancer cells=always multiplying, need lots of nucleotides
lipids=need lipids to make membrane
very active pathway needed for DNA synthesis
how does NADPH protect against red blood cell hemolysis?
red blood cells need to keep glutathione high, which prevents peroxide mediated cell lysis
NADPH is needed in the reaction to produce glutathione
thus, if you have a deficiency in G6PDh, low NADPH, low ability to keep glutathione high, the cell cannot handle extra oxidants, damage to cell membrane and lysis
what is the irreversible rate limiting step of the PPP?
the first step
conversion of G6P into 6phosphogluconone beta lactone by glucose-6-phosphate dehydrogenase (G6PDH)
produces one NADPH
highly specific to NADP+
strongly allosterically inhibited by NADPH, which is what regulates the entire process
how many molecules of G6P do u need to run the PPP?
3
what are the two outcomes of the PPP and what pathway do they lead back into?
either makes ribose-5-phosphate for nucleotide synthesis
or makes GAP to join back onto glycolysis
what is the purpose of the oxidative reactions in the PPP?
the purpose is NADPH production
what is the reaction/stoichiometry of the oxidative reactions?
how many NADPH are generated for each G6P used?
2NADPH are generated for each G6P used
what does isomerization mean?
interchange of groups between carbons
what is epimerization?
interchange of groups on a single carbon
what is the purpose of the isomerization and epimerization reaction?
the purpose is to make ribose-5-phosphate
what is the stoichiometry of the isomerisation and epimerization reaction?
what is the purpose and overall reaction of the C-C bond cleavage and formation reactions?
purpose is to recycle R5P and Xu5P
reaction:
R5P + 2Xu5P <-> 2F6P + GAP
this joins back into glycolysis
what are the enzymes of the C-C bond cleavage and formation reactions?
transketolase and transaldolase
which molecules determine the fate of G6P?
and what regulates those molecules
fate of G6P depends on the activity of
PFK, inhibited by ATP
G6PDH, inhibited by NADPH
this also depends on the cellular needs in ATP, NADPH and ribose-5-phosphate
what pathway is activated when the cell needs both NADPH and nucleotides?
NADPH and R5P made
excess R5P and Xu5P recycled back to F6P and GAP, for glycolysis
the PPP will be activated
what pathway is activated when the cell needs NADPH only?
NADPH and R5P are made
R5P and Xu5P are made back to F6P and GAP for glycolysis
no need for nucleotides so R5P is not used
what pathway is activated when the cell needs nucleotides only?
there is an abundance of NADPH which shuts off G6PDH
the PPP does not go ahead
the forward reaction doesn’t work
F6P and GAP are used for the synthesis of R5P by reversing the transketolase and aldolase reactions
