NS 3200 Professor Thalacker-Mercer Fall 2016
Week 2: Lecture 3 of 3 9/02/2016
Announcement: T.A.’s are both out next week, at a conference. Dr. Talacker-Mercer will have regular office hours.
● Glucose Metabolism Lecture 6
○ iClickr Question:
○ Pyruvate oxidized in the cytosol from lactate is converted to oxyloacetate in the mito- chondria
■ True
○ Increased Fructose 2,6 bisphosphate increases glycolysis and decreases gluconeogenesis?
■ True
○ When ATP is used faster than it is produced, which f the following will occur?
■ Phosphofructokinase-1 is activated
■ Gluconeogenesis activated
■ AMP levels are high
■ Gluconeogenesis inhibited
□ Anything anabolic is shut off, anything catabolic turned on.
○ Diagram labeling question slide 5, type of question on the exam.
■ 1 same enzyme, different isoforms. (positions G. and B.) PEPCK cytosol, is different from PEPCK mitochondria
■ 2 oxaloacetate is in what position? (A., H.) cannot cross over mitochondrial mem- brane, have to have 2 of them.
■ 3 dehydrogenase. (F. D.) dehydrogenase is the enzyme that deals with oxaloacetate.
■ 4 which series occurs in gluconeogenesis begins as lactate? (A, B, J PEP)
● Transcription Factors for Glucose Utilizing Pathways
○ DNA factors that bind to promoter to up-regulate the transcription of the gene.
■ ChREBP □ When phosphorylated kept in cytosol, cannot translocate to nucleus.
□ Active when glucose is high
□ Turns on expression of pyruvate kinase, and lipogenic genes
□ controlled by intermediates such as pentose
■ SREBP-1c
□ Activated by insulin
□ suppressed by glucagon and suppresses transcription factors for key gluco- neogenic enzymes.
● Transcription factors for glucose producing pathways
○ FOXO1 forkhead box protein 1
■ Turn on gluconeogenic enzymes
○ When phosphorylated, stays in cytosol
○ when glucose is low, insulin is low, dephosphorylated, and translocated to nucleus where in begins to transcribe for gluconeogenesis.
■ FOX01 is big in muscle atrophy
■ In an insulin insensitive person, would you expect FOXO1 to have increased or de- creased activity?
□ It will have more translocated into nucleus, causing muscle atrophy in diabetics.
● *Green means that it has a positive effect in slides.
● Coordinated Regulation of Opposing Pathways
○ High AMP glycolysis activated
● Insulin stimulates which transcriptional factors that promote glycolytic and lipogenic gene expression?
○ FOXO1
○ ChREB
○ SREBP-1c
○ None
● A lot of things feed into gluconeogenesis:
○ Similarly there are several amino acids that feed into pyruvate to get glucose, and some feed into oxaloacetate.
○ Why is it important fro multiple substrates for gluconeogenesis? So you can maintain 5 mM glucose for brain function and glucose homeostasis in the body.
○ Alanine (Cahill) Cycle
■ Lactate is converted back to glucose in a very costly process, feeding the system. ■ Transamination is where an amine group is transferred to convert pyruvate to ala- nine so it can move from muscle to blood to liver.
□ Nitrogen is passed and deaminated into urea, and alanine is converted back to pyruvate.
□ Uses 4 ATP.
□ Pyruvate still has to be converted back into glucose
□ NADH is retained, as long as O2 is sufficient
□ Removing nitrogen during strenuous activity.
○ Why did the Devlin book specifically highlight that the alanine cycle is specifically oc- curring?
■ Because both cycles Cory cycle and Alanine Cycle occur simultaneously.
● Glucose Metabolism in Various Tissues
○ Red blood cells do not have mitochondria, therefor pyruvate is converted to lactate for transport out of the cell
○ Brain uses glucose
○ muscle excretes lactate
○ liver has
■ glycogen synthesis,
■ pyruvate,
■ lactate entering,
■ glucose production,
■ pyruvate cleavage forming ATP.
□ Takes what it needs LAST
□ Bypass step 1 is most complicated for gluconeogenesis
● Thinking critically, what 2 problems might happen in a deficiency in PEPCK?
■ Hypoglycemic
■ Build up of lactate
○ What organ system is affected most?
■ Brain, neurons degenerate, severe neurological problems.
○ Glucose stores during fasting in the form of glycogen will run out within 24-48 hours.
● Why can the liver replenish blood glucose but skeletal muscle cannot?
○ Glucose 6 phosphatase has to be present to dephosphorylate
○ Muscles can store glycogen, but cannot perform gluconeogenesis because the tissue lacks the enzyme Glucose 6 Phosphatase. ■ In most cases the lipid droplet is next to the mitochondria
○ You hit a wall in exercise because you have depleted your glycogen stores in your mus- cles.
● Glycogen - Glucose Storage
○ Glycogen is stored in branched chains of glucose molecules, branches from the alpha 1,6 position.
● Glycogen Synthesis
○ glucose 6 phosphate can either go into glycogen synthesis,
○ phosphoglucomutase moves the phosphate to the 1 phosphate position
○ Glucose 1-phosphate uridyltransferase is needed to produce UDP-glucose
● Non-reducing end of glycogen chain, glucose is added to the non-reducing end, causing elon- gation.
● Glycogenolysis will occur when individual glucose molecules are removed from a chain, with the help of a phophorylase and a debranching enzyme, converted back to glucose1 phosphate, rearrangement of the phosphate group, back to glucose 6 phosphate, then the pentose 6 path- way.
● Phosphorylase will remove the phosphate to remove the last glucose molecule and phosphry- lates it.
○ Removal of glucose molecules on each branch. They will only reduce to 4 molecules, once it gets down to 4, the last 3 will be hydrolysed
● Glucose UDP is necessary to form and add the last glucose to the existing glycogen molecule.
● Glycogen phosphorylase + debranching enzyme
● Glycogen is well hydrated
○ Worth 3x own weight in water
○ Low carb diet causes glycogen stores to reduce, losing water weight.
● An individual with McArdle disease with a mutation in the muscle type glycogen phosphory- lase gene would be exercise intolerant?
○ True
○ Individuals can exercise for a little bit
● Skeletal muscle has glycogen stores to provide glucose for the body?
○ False
○ Muscle only provides glucose for itself.