01.03.12+-+Glycolysis


 * Glycolysis**


 * 1. Be able to calculate the number of moles of ATP generated when either glycogen or glucose is degraded to either lactate, or CO2 and H2O**

If a single unit of glycogen is degraded to lactate, it goes through these key steps: glucose-1-phosphate, glucose-6-phosphate, and then through glycolysis to pyruvate. The metabolism of glucose-1-phosphate to pyruvate produces 3 ATP and 2 NADH. In an anaerobic environment, the 2 NADH molecules are consumed in the reduction of pyruvate to lactate. The 3 ATP remain as the net product of glycogen to lactate.

If a single unit of glycogen is catabolized all the way to CO2, we can pick its course up at pyruvate, when it has already produced 9 ATP (3 substrate-level phosphorylations and 2 NADH). Two pyruvate molecules then go through pyruvate dehydrogenase (2 NADH produced) and the TCA cycle, which produces 2 GTP, 6 NADH, and 2 FADH2. We now have 9 ATP from glycolysis, 6 ATP from pyruvate dehydrogenase, and 24 (2 + 6*3 + 2*2) ATP from the TCA cycle. This gives us a net ATP production from glycogen-->CO2 and H2O of 39 ATP.

If glucose is taken through these same metabolic steps, just subtract 1 ATP from the total due to the first step performed by hexokinase: glucose + ATP --> glucose-6-phosphate + ADP glucose --> lactate = 2 ATP glucose --> CO2 + H2O = 38 ATP


 * 2. Name the "key" glycolytic and gluconeogenic enzymes, together with their substrates and products**

There are only a few glycolytic enzymes that could be clearly defined as "not key." The three definitively key ones are the regulatory enzymes of steps 1, 3, and 10.


 * Step 1 consumes an ATP
 * Hexokinase: glucose to glucose-6-phosphate
 * Step 3 consumes an ATP
 * Phosphofructokinase 1: fructose-6-phosphate to fructose-1,6-bisphosphate
 * Step 10 produces an ATP
 * Pyruvate kinase: phosphoenol pyruvate (PEP) to pyruvate

I also think that steps 4, 5, 6, and 7 play important roles:


 * Step 4 divides glycolysis into its first and second halves; it is the step where one molecule becomes two
 * Aldolase: glucose-1,6-bisphosphate to Dihydroxyacetone Phosphate and Glyceraldehyde-3-phosphate.
 * Step 5 is the one out of sequence step:
 * Triose phosphate isomerase: dihydroxyacetone phosphate and glyceraldehyde-3-phosphate.
 * Step 6 produces an NADH
 * Glyceraldehyde-3-phosphate dehydrogenase: glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate
 * Steps 7 produces ATP:
 * Phosphoglycerate kinase: 1,3-bisphosphoglycerate to 3-phosphoglycerate

There are 11 steps to gluconeogenesis. There are four new enzymes that replace the three regulatory enzymes of glycolysis


 * Pyruvate carboxylase and phosphoenol pyruvate (PEP) carboxykinase replace the irreversible pyruvate kinase (took PEP to pyruvate in the last step of glycolysis).
 * Fructose bisphosphatase replaces the irreversible phosphofructokinase 1 (took fructose-1-phosphate to fructose-1,6-bisphosphate in the 3rd step of glycolysis).
 * Glucose-6-phosphatase replaces the irreversible hexokinase (took glucose to glucose-6-phosphate in the 1st step of glycolysis)

Notice that:
 * Only steps 2, 8, and 9 of glycolysis were not mentioned: phosphoglucose isomerase, phosphoglycero-mutase, and enolase
 * All of the non-regulated steps of glycolysis (2, 4, 5, 6, 7, 8, and 9) are shared with gluconeogenesis.
 * The three regulated steps of glycolysis all use or produce ATP.
 * The one ATP involved step that is not regulated is step 7: phosphoglycerate kinase taking 1,3-bisphosphoglycerate to 3-phosphoglycerate
 * Steps 1 and 3 of glycolysis consume ATP: hexokinase and phosphofructokinase 1
 * The glycolytic enzymes shared with gluconeogenesis are named for their function in glycolysis


 * 3. Be able to identify the carbohydrate metabolic capacities of different cell types or tissues**

7 carbohydrate metabolic pathways: glycolysis, fermentation, TCA cycle, gluconeogenesis, pentose phosphate pathway (PPP), glycogen synthesis, and glycogenolysis

Brain Blood Liver Kidney Heart/Muscle tissue
 * The most selfish viral organ of the body that can basically only use glucose as an energy source
 * Consumes 75% of daily glucose
 * Can do glycolysis, PPP, and TCA cycle
 * Composed of anuclear erythrocytes
 * RBC can do glycolysis and PPP. If no PPP because of glucose-6-phosphate dehydrogenase deficiency, then at risk for drug-induced hemolytic anemia
 * The most generous of organs. Will work off many other energy sources than glucose during fasting.
 * Hepatocytes have glucokinase, a higher Km, higher Vmax isozyme for hexokinase. This means that it only turns on when blood glucose levels are high, but it clears out glucose quickly into...
 * Gluconeogenesis. The organ that provides the vast majority of the body's glucose during fasting over 20 minutes is the liver. Also reconverts lactate from anaerobic tissues to pyruvate.
 * Glycolysis. Only does glycolysis if glucose is present in excess. If the liver's pyruvate kinase is phosphorylated it is inactive, stranding PEP and allowing it to be reconverted through gluconeogenesis to glucose to be shipped to the rest of the body.
 * Does everything but fermentation (reverses fermentation)
 * Dr. Ullman talked about the kidney as a vestigial liver that had picked up a few other functions. I thought that was interesting.
 * Does everything but fermentation
 * Fermentation: conversion of pyruvate into lactate to recharge NAD+ under anaerobic conditions. Produces no ATP. Shouldn't happen in heart.
 * Can do everything but gluconeogenesis
 * It's important to note that while the liver and muscle tissues both synthesize and break down glycogen, muscle tissue uses glucose for itself, while liver ships it off to the blood.


 * 4. Given a set of circumstances (e.g., changed concentration of a substrate or effector or increased secretion of a hormone) you should be able to forecast the overall effect on the rate of glycolysis, gluconeogenesis, glycogenesis, and glycogenolysis**

A few examples of circumstances:

Fasting/Starvation High blood glucose (Fed state) Diabetic State Exercise State
 * Levels up: glucagon, epinephrine, glucocorticoids
 * Levels down: blood glucose, insulin, fructose-2,6-bisphosphate
 * Glycolysis continues in muscle and nervous tissue, but is shut down in the liver due to the high Km of glucokinase and the lack of the activator fructose-2,6-bisphosphate to counteract the inhibitory effects of ATP.
 * Gluconeogenesis occurs in the liver and kidney. The regulated enzymes (pyruvate carboxylase, PEP carboxykinase, fructose bisphosphotase, and glucose-6-phosphotase are activated/phosphorylated by glucagon and epinephrine by cAMP via Protein Kinase A. They are also allosterically activated by CoA derivatives and citrate. Where gluconeogenesis occurs (the liver), it is far more important to take whatever carbon is available and turn it back into glucose to ship to the brain and muscle tissue.
 * Glycogenolysis occurs in the muscles, liver, and kidneys. Activated by AMP.
 * Glycogenesis does not occur. Inhibited by A
 * Activity up: Fructose-2,6-bisphosphotase, enzymes of gluconeogenesis (pyruvate carboxylase, PEP carboxykinase, fructose bisphosphatase, glucose-6-phosphatase) and glycogenolysis (
 * levels up: insulin, blood glucose, fructose-2
 * levels down:

Substrates/effectors/hormones that were specifically mentioned as varying in levels:

Blood glucose ATP AMP Glucagon Epinephrine Insulin Fructose-2,6-bisphosphate Acetyl CoA


 * 5. Identify the enzymes responsible for the major controls involved in the above changes**


 * 6. Define high energy compounds**


 * 7.Know the metabolic fates of key branchpoint intermediates like glucose-6-phosphate and pyruvate**


 * 8. Name the first enzyme in the hexose monophosphate shunt and know the biochemical consequences of its deficiency**


 * 9. Define the overall function of the pentose phosphate pathway**


 * 10. Understand the benefits and costs of glycogen storage**


 * 11. Know the key reactions of glycogenesis and glycogenolysis and how they are regulated by allosteric effectors and reversible covalent modification.**


 * 12. Be able to describe the effects on glycogenesis and glycogenolysis of: hormones, calcium, resting, exercise, and specific enzyme defects such as the glycogen storage diseases (don't memorize their names).**