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What are the regulated steps in glycolysis? (Technically 3, but say 4) Name substrates and products too.
- 1. Hexo/glucokinase (Glucose --> G6P)
- 2. PFK1: F6P--> F1,6BP
- 3. Pyruvate kinase: PEP--> pyruvate
4. Pyruvate dehydrogenase
How long can glycogen stores provide glucose to peripheral tissues for between meals during a resting state?
How long after a meal does GNG start?
When does it reach full rate?
10-18 hours. (30 minutes in high intensity exercise)
Reaches full rate after glycogen stores are depleted
Where do all glycogen reactions take place? Apart from enzymes, what else does glycogenesis need? (2)?
Glycogenesis needs UDP-glucose (activated glucose) and glycogenin or residual glycogen.
- What enzymes are required? a1,#
- Need what else? (2)
- Starting substrate?
- Glycogen synthase (a1,4) - creates linear chain
- Branching enzyme (a,16) - cleaves 6-8 glucoses from linear chain and tacks on branch.
Also requires: UDP-glucose and glycogenin
Starting substrate: Glucose-6-P
1. Enzymes? (4)
2. Muscle vs. other organs? (which organs?) 3
3. Starting substrate?
4. Final product? (3 diff scenarios)
1. Enzymes: Glycogen phosphorylase, glucosyl transferase, debranching enzyme, glucose-6-phosphatase
2. Muscle (unlike liver, kidney and intestines) does NOT have G6Ptase, so cannot release free glucose into blood. All products of glycogenolysis go to glycolysis or whatever else.
- 3. Starting substrate: glycogen
- 4. After debranching enzyme: free glucose. In liver, kidney, intestines (w/ G6Ptase): free glucose. In muscle: G6P.
Regulation of glycogen metabolism:
1. Why regulate glycogen synthase and glycogen phosphorylase?
2. When do you want to increase degradation? Why? 3. 3. Do you care if it's fast or slow? (recall methods of long-term vs short-term regulation?
4. What hormones will this be present under?
- 1. To maintain homeostasis and to prevent wasting substrates and energy.
- 2. Increased degradation during fasting or exercise to maintain serum glucose levels.
- 3. We would want it to be fast during exercise and slow during fasting.
- 4. GLUCAGON, EPINEPHRINE, insulin
When do you want to increase synthesis of glycogen?
Do you care if it's fast or slow?
What hormone(s) will be present under this condition?
Will your answers be the same for liver and muscle?
- 1. During fed state when you have abundance of nutrients
- 2. We would want it to be slow to ensure peripheral tissues have enough time to uptake sufficient amounts of glucose.
- 3. INSULIN, glucagon
- 4. No, muscle will undergo glycogenolysis during exercise, while liver will break down glycogen faster in the resting state.
What happens to glycogen in fed state? 2
- 1. Insulin activates protein phosphatase 1, which destroys cAMP.
- 2. PP1 also dephosphorylates glycogen phosphorylase (inactive) and glycogen synthase (active)
What happens to glycogen during fasting? 3
- 1. Glucagon & epinephrine use cAMP mechanism forming ATP--> cAMP
- 2. cAMP activates cAMP-dep protein kinases (PKA)
- 3. Protein kinases phosphorylate glycogen phosphorylase (activating) and glycogen synthase (deactivating)
What happens to glycogen during exercise?(3)
- 1. Muscle contraction activates release of Ca2+ from SR
- 2. Ca2+ binds to Ca2+-dep kinase that can phosphorylate (like PKA), glycogen synthase and phosphorylase, activating glyc phosphorylase.
- 3. AMP: extreme anoxia or depletion of ATP, AMP activates glycogen phosphorylase w/o it being phosphorylated!
Draw the regulation of glycogen metabolism.
5 glycogenolysis enzymes
2 glycogenesis enzymes
What happens to glycogen in the liver: (1) After a meal (2) After fasting for 6 hrs (3) 24 hrs (4) 36 hrs?
- (1) Insulin activates PP1, destroys cAMP --> activates glycogen synthase, deactivating glycogen p'lase.
- (2) Glycogolysis: Glucagon activates cAMP --> PKA --> glycogen phoshporylase and turns of glycogen synthase.
- (3) 24 hrs - glycogen will have been depleted --> gluconeogenesis.
- (4) 36 hrs - same as 24 hrs
What happens to glycogen in the MUSCLE: (1) After a meal (2) After fasting for 6 hrs (3) 24 hrs (4) 36 hrs?
(1) Insulin activates translocation of GLUT4, allowing uptake of glucose into muscle --> glycogenesis in muscle.
Time points don't really matter - all that matters is whether exercise occurs and for how long/what intensity.
How is glycogen affected during exercise:
3. Energy deficit (what's special about this)
- 1. Epinephrine is major hormone
- 2. Muscle contraction --> Ca2+ release from SR --> binds & activates calmodulin subunit of Ca2+-dep kinase
- This kinase p'lates as if glucagon, cAMP, PKA were present.
- 3. Energy deficit --> high AMP:ATP ratio during extreme anoxia or depletion of ATP, AMP can activate glycogen phosphorylase w/o phosphorylation. This is much faster & is independent from glucagon!
T1D vs. T2D:
Description of both.
What is T2D associated with?
What is clinical presentation of T1D?
What happens to pancreas in T2D?
What are cutoff glucose and HbA1C values for diabetes?
- T1D: chronic, autoimmune disease associated with progressive destruction of b-cells in pancreas.
- T2D: Characterized by progressive insulin resistance.
T2D is associated w/ old age, obesity, rare genetic defects.
Pancreas: amyloid replacement of cells in islet of T2D--> fibrous proteins aggregate in 90% of T2D islets.
Cutoff values: >126 mg/dl and >6.5. Prediabetes: 100-125 or 5.6-6.4
How is glycolysis regulated? (5)
- 1. Glucose uptake by cells (transporters)
- 2.Allosteric reg of GK, HK, PFK
- 3. Hormonal regulation of key enzymes by carb rich diet vs. fasting
- 4. Short-term via action on pyruvate kinase of insulin vs. counterregulatory enzymes
- 5. Long-term (gene transcription) of glucokinase, PFK-1, and pyruvate kinase in liver. High CHO increases and fasting/glucagon suppresses synthesis.
What are the 5 GLUT transporters?
1. Which are regulated by insulin?
2. Present on muscle cells/adipocytes/cardiomyocytes?
- 1. GLUT 4
- 2. GLUT 4
- 3. GLUT 2
- 4. GLUT 2
What are the regulatory enzymes in glycolysis?
Gluco/hexokinase, PFK-1, pyruvate kinase (PDH)
What are the regulatory enzymes in TCA cycle? What are the products of TCA cycle from one glucose?
Citrate synthase, isocitrate/a-ketoglutarate dehydrogenase.
Products: 3 NADH (3 ATP), 1 FADH2 (1 ATP), 1 GTP DOUBLED!!!!
What happens if there's no O2 for ETC?
Reduced coenzymes will be backed up - buildup of NADH will inhibit TCA cycle and body will rely on anaerobic glycolysis
What inhibits ETC?
1. NADH DH
2. What else?
3. cytochrome oxidase
4. ATP synthase
- 1. Barbituates
- 2. Uncouplers - increase permeability of inner mitochondrial membrane, decreasing proton gradient, decreasing ability for ATP synthase to generate ATP i.e. aspirin (seen in brown adipose tissue for thermogenesis)
- 3. CO, H2S, cyanide
- 4. Olygomycin blocks proton channel.
How many H+ needed for each ATP made? At which points are H+ transported across membrane? (3) At what point does oxygen accept final electrons?
NADH DH, Cytb--> Cytc, Cyta.a.3 (cytochrome oxidase)
At cytochrome oxidase
What happens when there are mutations in mtDNA? What organs are most effected? (2) why?
Human disease - skeletal muscle and brain, bc they use the most energy and have the most need for functioning mitochondria.
Summary of Cellular Respiration:
(1) Total chemical equation
(2) Glycolysis: substrates and products
(2) 6C glucose --> 2 3C pyruvate + 2 ATP + 2 NADH
(3) 2 3-C pyruvate --> 2 Acetyl CoA + 2 NADH
(4) TCA: 2 Acetyl CoA --> 4CO2 + 6NADH + 2 FADH2 + 2GTP (ATP)
(5) 10 NADH + 2 FADH2 --> 34 ATP + H2O
What are the 3 major pathways for Glucose-6-P?
- 1. Glycolysis
- 2. Glycogen
- 3. PPP
What is the purpose of the PPP? (3 main ones)
- 1. To produce NADPH
- 2. Xylulose 5 P - activator of ChREBP
- 3. Ribose-5-P for synthesis of nucleotides and nucleic acids.
What is the purpose of NADPH?(3)
- 1. Synthesis of FAs and steroids
- 2. Regeneration of reduced glutathione (GSH) in reaction
- 3. Detoxification of H2O2 in RBCs by glutathione peroxidase-glutathione reductase system.
Where does gluconeogenesis take place? (during a lengthy fast?) What substrates can be used? (4 most common)
Summary of pathway? 4 to 1
Where does energy to fuel GNG come from?
Lactate, glycerol, glucogenic amino acids (alanine and glutamine)
2 pyruvate + 4 ATP + 2 GTP + 2 NADH --> glucose
Draw fasting and fuel sources over 0-24 hrs and 2-40 days for glucose.
Draw energy sources over two weeks of fasting.
What are the four regulated irreversible enzymes in GNG?
What intermediates and products does shifting the equilibrium to GNG favor? (3)
- 1. Pyruvate carboxylase
- 2 PEPCK
- 3. F1,6BPtase
- 4. Glucose6Phosphatase
Pushes towards irreversible formation of PEP, F6P, glucose
How is GNG regulated? (5)
- 1. Availability of GNG precursors (GNG AAs from protein when blood glucose levels/insulin levels are low)
- 2. Availability of energy (needs 12 ATP for each glucose synthesized)
- 3. Glucagon (bifunctional enzyme, inhibits PDH kinase)
- 4. Acetyl CoA - allosterically activates pyruvate carboxylase (AND INHIBITS PDH).
- 5. Pyruvate kinase - deactivated by glucagon
- 6. AMP:ATP ratio: High activates PFK-1, low inhibits F1,6BPtase. Adiponectin activates AMPK which inhibits tx of G6Pase and PEPCK.
How does glucagon regulate GNG? (3)
1. Lowers F2,6BP --> activating F1,6BPtase and inhibiting PFK-1 favoring GNG>glycolysis
2. Covalent modification of enzyme activity: inactivates hepatic pyruvate kinase, decreasing PEP--> pyruvate so PEP can be used for GNG
3. Induction of enzyme synthesis: Glucagon increases transcription of PEPCK gene. Insulin decreases transcription of this gene.
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