unit 18 : glucose metabolism Flashcards
Name the order of enzymes in glycolysis
hexokinase
phosphoglucose isomerase
PFK (phosphofructose kinase-1)
Aldolase
Triose phosphate isomerase
Glyceraldehyde 3-phosphate dehydrogenase
phosphoglycerate kinase
phosphoglyceromutase
enolase
pyruvate kinase
Name the reaction products in glycolysis (in order)
Glucose 6-phosphate
Fructose 6-phosphate
Fructose 1, 6-bisphosphate
DHAP and Glyceraldehyde 3-phosphate *G3P is the only product that can move forward (this part happens twice)
1,3-bisphosphoglycerate
3-phosphoglycerate
2-phosphoglycerate
Phosphoenolpyruvate
Pyruvate
what are the irreversible steps of glycolysis
step 1 (hexokinase)
step 3 (PFK-1)
step 10 (Pyruvate kinase)
what steps require ATP and what steps produce it
require/investment:
Step 1 (hexokinase
Step 3 (PFK-1)
produce it:
step 7 (phosphoglycerate kinase)
step 10 (pyruvate kinase)
oxidation/reduction steps
step 7: NAD is reduced to NADH and glyceraldehyde 3- phosphate is oxidized to 1,3-BPG
STEP 9: H2O is produced
enzymes required to digest dietary carbs
a-amylase
a-glucosidase
a- dextrinase (isomaltase)
maltase
sucrase
lactase
Allosteric regulation of muscle PFK-1:
inhibited by high ATP
- lowers affinity to F6P
activated by high levels of AMP
Inhibition by ATP greater at lower pH
(muscle isoform only)
– Reduces further accumulation of excess acids in muscle
Allosteric Regulation of Liver PFK
Regulated by energy charge
– Inhibited by ATP
– Activated by AMP
Inhibited by citrate (TCA cycle)
Activated by Fructose 2,6-bis-P
– Produced by PFK-2 at high blood glucose levels
– Reduces inhibitory effect of ATP
– Increases affinity for fructose 6-P
example of Feedforward activation
Effects of glucagon and insulin on PFK-1 in liver
-glucagon deactivates PFK-1
- insulins activates PFK-1
Allosteric Regulation of Hexokinase
- high levels of G6P inhibit
- Indirect control by phosphofructokinase activity
– Accumulation of fructose 6-P by low PFK-1 activity leads to reversible conversion to Glucose 6-P
describe hexokinase isoenzymes
- 4 different isozymes in humans
- G6P inhibits I, II, III, but not IV (glucokinase a liver isoform)
- Allows high levels of glucose 6P in liver
there are different Km’s for Hexokinase of glucose?
true
– Hexokinase I: KM~ 0.2 mM
– Hexokinase IV: KM ~ 10 mM
** Significant activity only at very high glucose concentrations
allosteric regulation of pyruvate kinase
- inhibited by high levels of ATP, acetyl Co-A and alanine
high acetyl-coa concentration says there’s a lot of energy and TCA is backed up
alanine is a derivative of pyruvate. it indicates high pyruvate concentration
Control of Glycolysis by Compartmentalization
- Uptake of glucose from blood by passive transport
- several glucose transporter (GLUT) Isoforms with different KM
– GLUT1 (most cells): KM ~3mM < typical concentration in blood
- Active even at low blood glucose levels
– GLUT2 (liver, pancreas): KM ~20 mM»_space; typical concentration in blood
- Active only at high blood glucose levels;
- Removes excess glucose when glucose levels are high
- Low activity at low blood glucose levels prevents ‘syphoning’ off glucose from brain and muscles at fasting conditions
- Increased expression in cancer cells
Regulation of Glycolysis by Transcriptional Control
Regulate expression of glycolytic enzymes
– Glucokinase
– PFK-1
– Pyruvate kinase
regulated by hormones insulin and glucagon
describe bypassing step 10 in gluconeogenesis
Pyruvate carboxylase rxn
- Pyruvate transported into mitochondria
- converted from C3 to C4 in mitochondria by carboxylation
- Biotin used as prosthetic group
– Driven by ATP cleavage
– Allosteric activation by acetyl-CoA
PEP carboxykinase rxn
- occurs in cytoplasm
- Shuttling of oxaloacetate to Cytoplasm via malate-aspartate shuttle
describe Bypassing Step 3 in gluconeogenesis
-Fructose 1,6-BP converted to F6P by fructose 1,6-bisphophatase
- hydrolysis rxn
- Regulatory function in gluconeogenesis
–Inhibited by Fruc 2,6-BP
describe bypassing step 1 in gluconeogenesis
- Glucose 6-P converted to glucose by glucose 6-phosphatase
- occurs in ER lumen
gluconeogenesis rxn
2 pyruvate + 4 ATP + 2 GTP + 2 NADH + 2 H + 2 H2O = Glucose + 4 ADP + 4 Pi + 2 NAD+
6 NTPs consumed (net)
allosteric regulation of gluconeogenesis
Fructose 1,6-BP:
inhibited by high levels of AMP and F 2,6-BP
Pyruvate carboxylase
activated by acetyl-CoA
Control of Blood Glucose Level by Liver - High Blood Glucose
- Increased uptake by additional glucose transporter (GLUT2)
Increased rate of glycolysis and glycogen synthesis
– Inhibition of glycogen phosphorylase
Decreased gluconeogenesis
– Increased F 2,6BP
Control of Blood Glucose Level by Liver – Low Blood Glucose
- Increased glycogenolysis
and gluconeogenesis
– precursors: Lactate, glucogenic amino acids, glycerol - Reduced glycolysis due to lower levels of fructose 2,6-BP
-Hydrolysis of glucose 6P by phosphatase to glucose - GLUT2 releases glucose into blood
Phases of Pentose Phosphate Pathway
oxidative phase
- provides NADPH in 2 oxidation steps
- converts G6P to ribulose 5P
- irreversible rxns
- regulated
non oxidative phase
- converts ribulose 5P to other sugars
- Ribose 5P
- Fructose 5P, GA3P or other sugars
- reversible
net reaction of the oxidative phase of PPP
G6P + 2 NADP+ + H2O = Ribulose5P + 2 NADPH + H + CO2
what do transketolases do and transaldolases do?
transketolases move 2 carbons
transaldolases move 3 carbons
what are the main reactions of the oxidative phase of PPP
- Glucose-6 phosphate dehydrogenase
- 6-phosphogluconate dehydrogenase
enzymes involved in non oxidative phase of PPP
– Transketolase
– Transaldolase
– Isomerases - rearranges a molecules
– Epimerases- changes the arrangement of one carbon
regulation of PPP
Glucose 6P DH inhibited by NADPH
- Low NADPH/NADP+ ratio
→ flux of Glucose 6P into PP pathway
– High NADPH/NAD+ ratio
→ reduced flux of Glucose 6P into PP pathway and increased flux into glycolysis. need ATP instead
Non-oxidative phase reactions reversible
– Controlled by substrate availability
what is the role of NADPH in ROS detoxification
Glutathione is an important ROS Scavenger
- NADPH reduces GSSG
- regenerates by reducing GSSG to GSH
reaction goes from
GSH + H2O2 = GSSG + 2 H2O via glutathione peroxidase
what is the purpose of the PPP
- produce NADPH and Ribulose 5-phosphate
- NADPH produces reducing power for biosynthesis
- Ribulose 5-phosphate for nucleic acid synthesis
