glucose metabolism Flashcards
malate-aspartate shuttle (location, ATP yield)
heart and liver
32 ATP
glycerol-3-phosphate shuttle (location, ATP yield)
muscle
30 ATP
hexokinase (when used, where, affinity/vmax, regulated by)
when glucose is low
ubiquitous
high affinity, low Vmax
feedback inhibition by glucose-6-P, not affected by insulin
glucokinase (when used, where, affinity/vmax, regulated by)
when glucose is high
liver, pancreatic B cells
low affinity, high Vmax
induced by insulin
glucokinase mutation leads to
MODY (maturity onset DM of young)- decreased B-cell metabolism of glucose leads to decreased insulin secretion, DM is worse in pregnancy
2 steps of glycolysis that require ATP
glucose –> glucose-6-P (by hexokinase)
fructose-6-P –> fructose-1,6-bisP (PFK-1)
regulators of PFK-1
(+) fructose-2,6-bisP, AMP
(-) ATP, citrate
regulators of pyruvate kinase
(+) fructose-1,6-bisP
(-) alanine, ATP
effect of pyruvate kinase deficiency
decreased ability to convert PEP –> pyruvate
RBCs are most vulnerable
decreased ability to make ATP + decreased activity of Na/K ATPase = cell swelling/lysis = hemolytic anemia
fate of fructose-2,6-bisP in the fasting state
fasting = increased glucagon levels = increased cAMP = increased protein kinase A = phosphorylate and activate fructose-2,6-bisphosphatase= removes P to form fructose-6-P –> gluconeogenesis (decreased glycolysis)
fate of frucotose-6-P in fed state
fed = high insulin = decreased cAMP/protein kinase A = active PFK-2 = increased fructose-2,6-bisP = increased PFK-1 activity (increased glycolysis)
5 cofactors required for pyruvate dehydrogenase complex
TPP lipoic acid CoA FAD NAD
mnemonic for 5 cofactors fo PDH complex
TLC For Nobody
effect of arsenic
inhibits lipoid acid= rice water stools, garlic breath
what other enzyme complex uses same 5 cofactors at PDH complex?
a-ketoglutarate dehydrogenase
3 factors that increase activity of PDH-C
high calcium
high ADP
high NAD+/NADH
effects of pyruvate dehydrogenase deficiency
backup of pyruvate and alanine, leading to lactic acidosis
cause of pyruvate dehydrogenase deficiency
X-linked (gene for E1-alpha subunit) or acquired (thiamin def in alcoholism)
symptoms of pyruvate dehydrogenase deficiency
neurologic defects starting in infancy
treatment for pyruvate dehydrogenase deficiency
ketogenic diet (high fat, increased lysine, leucine)
2 purely ketogenic amino acids
lysine, leucine
4 fates of pyruvate
1) alanine via ALT (transfer of amino groups to liver)
2) oxaloactate via pyruvate carboxylase (gluconeogensis)
3) lactate via lactic acid dehydrogenase
4) actely-CoA via pyruvate dehydrogenase (TCA cycle)
lactate dehydrogenase deficiency
symptoms pronounced in times of decreased O2 (anaerobic exercise), inability to regenerate NAD+, leads to muscle breakdown
3 irreversible enzymes in TCA cycle
citrate synthase
isocitrate dehydrogenase
a-ketoglutarate dehydrogenase
NADH enters ETC at
complex I- NADH dehydrogenase
FADH2 enters ETC at
complex II- succinate dehydrogenase
other name of complex III
cytochrome bc1
other name of complex IV
cytochrome C oxidase
other name of complex V
ATP synthase
inhibitors of complex I (3)
rotenone
amytal
MPP
inhibitor of complex III (1)
antimycin A
inhibitors of complex IV (4)
CN
CO
H2S
N3-
inhibitor of complex V (1)
oligomycin
uncoupling agents (3)
aspirin, thermogenic, 2,4-DNP
effect of uncoupling agents
increase permeability of the inner membrane, leads to dissipation of the H gradient and decreased ATP synthesis/increased heat production
4 irreversible enzymes of gluconeogenesis, sites of action
1) pyruvate carboxylase- mitochondria
2) PEP carboxykinase- cytosol
3) fructose-1,6-bisphosphatase- cytosol
4) glucose-6-phosphatase- ER
where does gluconeogenesis occur? (3)
mainly liver, also kidney and intestinal epithelium
what fatty acids can contribute to gluconeogenesis?
odd chain FA- yield 1 propionyl-CoA during metabolism which will enter the TCA cycle as succinyl-CoA –> oxaloacetate –> gluconeogenesis
3 products of HMP shunt (oxidative)
2 NADPH
CO2
ribulose-5-P
3 products of HMP shunt (non-oxidative)
ribose-5-P
glycerol-3-P
Fructose-6-P
how will the cell accommodate a high demand for NADPH?
convert fructose-6-P to glucose-6-P for use in HMP shunt
describe the consequences of G6PD deficiency
G6PD is used to make NADPH
NADPH is important for the regeneration of reduced glutathione (GSH) from oxidized glutathione (GSSG)- GSH is used by glutathione peroxidase to neutralize H2O2 and prevent oxidative damage to cells = without G6PD, cells are increasly vulnerable to oxidate stress = hemolysis
triggers for hemolysis in G6PD(6)
fava beans INH sulfa drugs dapsone primaquine nitrofurantoin
inheritance for G6PD deficiency
X-linked recessive
survival advantage for G6PD deficiency
malaria resistance
blood smear findings in G6PD deficiency
heinz bodies- precipitation of oxidized hemoglobin
bite cells - from removal of heinz bodies by splenic macrophages
what are the steps that lead to glycogenolysis?
- fasting state leads to increased glucagon and epinephrine
- stimulate adenylate cyclase = increase cAMP –> increase protein kinase A
- protein kinase A phosphorylates glycogen phosphorylase kinase (active state) –> phosphorylates glycogen phosphorylase (active) = glycogenolysis
what are the steps that stop glycogenolysis?
- fed state leads to increased insulin
- insulin binds to tyrosine kinase receptor= dimerizes
- protein phosphatase is activated which removes phosphate from BOTH glycogen phosphorylase kinase and glycogen phosphorylase = stopping glycogenolysis
alternative route for glycogenolysis stimulation in muscle
calcium and calmodulin can activate glycogen phosphorylase kinase
bonds in glycogen (2)
a1,4- linear molecule
a1,6- branches
use of glycogen in muscle
used during exercise to supply muscle only
use of glycogen in liver
used to maintain blood glucose
what is the substrate for glycogen synthesis?
UDP-glucose (made by UDP-glycogen pyrophosphorylase)
cofactor required for glycogen phosphorylase
B6
role of deb ranching enzyme
at 4 glucoses away from branch point, deb ranching enzyme moves all glucose of the branch (except one) to the end, allowing glycogen phosphorylase to continue
alternative site for glycogen degradation, enzymes
in lysosomes using a1,4 glycosides
enzyme deficit in von gierke disease
glucose-6-phosphatase
symptoms of von gierke disease
severe fasting hypoglycemia
increased blood lactate
increased glycogen in the liver/hepatomegaly
enzyme deficit in pompe disase
lysosomal a1,4-glucosidase
symptoms of pompe disease
cardiomegaly
organomegaly
2 forms of pompe disease
infantile- more severe
adult- slow onset weakness, death from respiratory failure
enzyme deficit in cori disease
debranching enzyme
symptoms of cori disease
similar to von gierke, but less severe because it does not affect gluconeogenesis
no increase in blood lactate
enzyme deficit in McArdle’s disease
skeletal muscle glycogen phosphorylase
symptoms of McArdle’s disease
increased glycogen in muscle
painful cramps, myoglobinuria with strenuous exercise
