Chapter 16 Flashcards
(36 cards)
1
Q
Why is Glucose the Prominent Fuel?
A
- may have been available for primitive biochemical systems because it can form under prebiotic conditions
- most stable hexose
- low tendency to nonenzymatically glycosylate proteins
2
Q
Basis of Glycolysis
A
- Starts with 1-Glucose (6-Carbons) converted to 2 pyruvate (3-Carbons
each) - 2 ATP generated
- Location: cytoplasm
- Multiple Enzymes
3
Q
Stages of Glycolysis
A
- Investment stage
- Yield stage
4
Q
Investment stage
A
- traps glucose in the cell
- modification to split into a pair of phosphorylated
3-carbon compounds - uses 2-ATP to prime the pathway
5
Q
Yield stage
A
- oxidizes the 3-carbon compounds to pyruvate
- generating 2-molecules of ATP per 3-carbon
compound - 4-ATP total
- Net yield : -2 + 4 = 2-ATP
6
Q
Stage 1 – Reaction 1
A
Hexokinase
- traps glucose in cell by forming G-6-P (glucose-6-phosphate)
- cost: 1-ATP
- enzyme activity requires Mg2+ or Mn2+ as a cofactor to catalyze the reaction.
- substrate-binding induced fit to minimize hydrolysis of ATP.
- irreversible reaction
- regulator step
7
Q
Stage 1 – Reaction 2
A
- glucose 6-phosphate is converted into fructose 6-phosphate
- catalyzed by phosphoglucose isomerase
- reversible reaction
8
Q
Stage 1 – Reaction 3
A
- fructose 6-phosphate is converted into fructose 1,6-bisphosphate
- enzyme: phosphofructokinase (PFK).
- reaction is irreversible
- regulator step/commitment step
9
Q
Stage 1 – Reaction 4
A
- fructose 1,6-bisphosphate is split into two 3-carbon molecules
- dihydroxyacetone phosphate (DHAP; ketone)
- glyceraldehyde 3-phosphate (GAP; aldehyde) - enzyme: aldolase
- reaction is reversible
10
Q
Stage 1 – Reaction 5
A
- dihydroxyacetone phosphate (DHAP) into glyceraldehyde 3-phosphate (GAP)
- enzyme: triose phosphate isomerase
- reversible isomerase reaction
11
Q
Stage 2 – Reaction 1
A
- glyceraldehyde 3-phosphate into 1,3-bisphosphoglycerate
- enzyme: glyceraldehyde 3-phosphate dehydrogenase
- reaction: reversible
- oxidation-reduction reaction generating NADH
12
Q
Glyceraldehyde-3-phosphate dehydrogenase
A
- Multiple steps together
- Requires NAD+ as a coenzyme
- 2 steps involved
1. favorable oxidation of an aldehyde
2. unfavorable acyl phosphate formation - Reactions coupled through thioester intermediate
- Oxidation energy of 1st reaction captured to drive 2nd reaction
13
Q
Stage 2 – Reaction 2
A
- 1,3-bisphosphoglycerate into 3-phosphoglycerate
- 1,3-bisphosphoglycerate high phosphoryl-transfer to generate ATP
- enzyme: phosphoglycerate kinase
- reaction is reversible
- ATP generated via substrate level phosphorylation
14
Q
Stage 2 – Reactions 3, 4, 5
A
- 3-phosphoglycerate into 2-phosphoglycerate via phosphoglycerate via mutase
- 2-phosphoglycerate to phosphoenolpyruvate (PEP) via enolase
- phosphoenolpyruvate to pyruvate via pyruvate kinase generates ATP
15
Q
Irreversible reactions during glycolysis
A
reaction 1, 3, 10: all phosphoryl transfer reactions
16
Q
NAD+ → NADH + H+
A
- NAD+ is a necessary coenzyme for glycolysis
- recall: niacin (Vit B3) is an important component of NAD+
- Pyruvate metabolism
- recover NAD+ from NADH
- 3 possible fates: Ethanol, Lactate, Acetyl-CoA
17
Q
Lactate Production is Fermentation
A
- Occurs in humans under anaerobic conditions
- Allow activity to exceed O2 demand temporarily
- Bacteria
- Lactobacillus in microflora, food pickling
18
Q
Ethanol Production to Regenerate NAD+
A
- pyruvate decarboxylate generates acetaldehyde
- generates CO2 (would normally diffuse away)
- acetaldehyde then converted to ethanol via alcohol dehydrogenase
- NAD+ restored (glycolysis can continue)
19
Q
Glycolysis and Other Sugars
A
- Fructose and galactose from the diet
can be converted into glycolytic
intermediates
20
Q
Fructose
A
- Fructose-6-phosphate is in glycolytic pathway
- can be generated by some tissue cells BUT not liver
- In liver, fructose-1-phosphate is made via
fructokinase - fructose-1-phosphate split into DHAP and glyceraldehyde
- glyceraldehyde converted to glyceraldehyde-3-phosphate via triose kinase
21
Q
Clinical Insight: Excessive Fructose Consumption
A
- Excess fructose consumption has been linked to obesity, fatty liver, and the development
of type 2 diabetes - Partly because the manner in which fructose is processed in the liver
- High hepatic uptake of fructose
- Key regulatory enzyme of glycolysis, phosphofructokinase, is bypassed
- Leads to synthesis of excess acetyl CoA, that leads to fatty acid production
- Glyceraldehyde produced can get converted to glycerol for triacylglycerol synthesis
22
Q
Galactose
A
converted into glucose-6-phosphate by the galactose-glucose interconversion pathway
- can function in reverse to make galactose from glucose
23
Q
Phosphorylation (galactose–glucose interconversion pathway)
A
converts galactose to Galactose 1-
phosphate via galactokinase
24
Q
Add uridyl group (galactose–glucose interconversion pathway)
A
generates UDP-galactose via galactose 1-
phosphate uridyl transferase
- generates glucose-1-phosphate
25
Epimerization (galactose–glucose interconversion pathway)
UDP-galactose converted into UDP-glucose via
UDP-galactose-4-epimerase
26
Isomerization (galactose–glucose interconversion pathway)
glucose 1-phosphate into glucose 6-
phosphate via phosphoglucomutase
27
Clinical Insight: Lactose Intolerance
- inability to digest lactose
- low lactase activity
- lactose can not be absorbed
- fermented into lactate, methane and hydrogen
28
Regulating Glycolysis
- Regulatory control at the sites of the Irreversible reactions
- 3 irreversible enzymes of glycolysis:
1. Hexokinase
2. Phosphofructokinase
3. Pyruvate kinase
29
Regulation can be
tissue dependent:
- muscle glycolysis: regulated to meet need for ATP for contraction
- liver glycolysis: regulation to meet diverse roles including blood glucose maintenance
- Reversible reactions follow flow dictated by controlled irreversible reactions
30
Regulating Glycolysis: Phosphofructokinase (PFK) (muscle)
- Phosphofructokinase (PFK) Main control of glycolysis in mammals
- recall: F-6-P → F-1,6-bP
- ATP inhibits (also a co-substrate)
- AMP stimulates
- AMP used instead of ADP due to the activity of
adenylate kinase
- adenylate kinase can form ATP from ADP
31
Regulating Glycolysis: Hexokinase (muscle)
- Hexokinase is feedback inhibited by its product (Glucose-6-P)
- A build up of glucose-6-P (G-6-P) indicates that the cell no longer needs glucose
- The inhibition of PFK will lead to the inhibition of hexokinase
- PFK is the key enzyme (commitment step) of glycolysis
- G-6-P is also a substrate for glycogen synthesis
32
Regulating Glycolysis: Pyruvate Kinase (muscle)
- Pyruvate kinase: Phosphoenolpyruvate → Pyruvate
- If there is excess ATP: no need to make more → pyruvate kinase is inhibited
- If there is excess pyruvate: alanine synthesized from pyruvate by adding an amine
- Reaction occurs when high pyruvate levels
- Alanine inhibits pyruvate kinase
- If there is excess fructose-1,6-bisphosphate, which indicates a build up of an upstream precursor, this will stimulate the enzyme pyruvate kinase to keep up
33
Liver Glycolysis - Phosphofructokinase
- Citrate inhibits phosphofructokinase
- Fructose-2,6-bisphosphate stimulates phosphofructokinase
- Produced when there are high amounts of F-6-P
- ATP regulation still exists, but it is not as critical as in muscle
34
Liver Glycolysis - Glucokinase
- Hexokinase is an allosteric enzyme in the liver just as it is in muscle cells
- primarily responsible for phosphorylating glucose in the liver is glucokinase
(hexokinase IV)
- Glucokinase is active only after a meal, when blood glucose levels are high.
- Lower affinity for glucose than hexokinase (higher KM)
- Spares glucose for other tissues (brain/muscle)
- Uptake only when blood glucose concentrations are high
- Not inhibited by glucose-6-phosphate
- Allows enzyme to continue to trap glucose in liver at high concentrations
- Glycogen storage/fatty acid synthesis
35
Liver Glycolysis – Pyruvate Kinase
- Pyruvate kinase is allosterically regulated in the liver the same as in muscle
- Inhibitors: Alanine, ATP
- Activators: Fructose-1,6-bisphosphate
- Phosphorylation site in liver isoenzyme
- Phosphorylation shuts enzyme off
- Triggered by glucagon signalling in response to low blood glucose
- Mechanism to spare blood glucose for tissues other than the liver
36
Glucose Sensing and Insulin Release
* Insulin secreted by β cells of pancreas when blood levels of glucose are high.
* This secretion is stimulated by the metabolism of glucose by the β cells.
* Glucose enters β cells through GLUT2
* The increase in ATP closes a K+ channel, which alters the charge across the cell membrane.
* This alteration in turn opens Ca2+ channels.
* The influx of Ca2+ ions stimulates the release of insulin.
