Flashcards in Metabolism and Glycolysis Overview Deck (99):
What role does NAD+ and NADP+ play in many biologic reactions?
They are two of the most important electron carriers. They are needed as oxidizing reagents
What are the three end products of metabolism?
ATP, CO2 and H2O
Metabolic pathways process the major products of digestion of carbohydrates, lipids and proteins into what common product?
Where is acetyl CoA generated?
What does it mean that Acetyl CoA is the "common fuel"?
Acetyl CoA is the common end product of digestion of many different molecules that can enter the citric acid cycle and give rise to energy production through ATP
Where does the conversion of pyruvate to acetyl CoA take place?
The mitochondrial matrix
What is the primary fate of acetyl CoA?
oxidation in the TCA cycle for energy genteration
Other than oxidation in the TCA cycle, what are three other fates of acetyl coA?
1. Lipogenesis- formation of fatty acids
2. Ketogenesis- formation of ketone bodies
3. Cholesterologenesis- fomrations of cholesterol which can then be synthesized into steroids
- Acetyl CoA is a precursor for cholesterol-
How are excess carbohydrates stored?
Excess carbohydrates are stored as glycogen.
Where is glycogen usually stored?
The liver, and skeletal/heart muscles have the largest glycogen stores
What is the purpose of glycogen storage in the liver?
Glycogen is stored in the liver to be used as glucose by the rest of the body later on.
How are fatty acids processed to become acetyl-CoA?
Fatty acids go through beta-oxidation in the mitochondria to form acetyl-CoA
Can all cells metabolize fatty acids?
No- only cells that have mitochondria can have beta-oxidation and therefore metabolize fatty acids
How are excess fatty acids stored?
Fatty acids are stored as triacylglycerols in adipose tissue
In what form are carbohydrates metabolized?
Carbohydrates are broken down into glucose and then metabolized to form acetyl CoA
How are excess amino acids stored?
Amino acids are stored as protein
How are amino acids catabolized?
Amino acids are metabolized either to acetyl CoA or an intermediate in the citric acid cycle
Catabolism of what leads to the production of ammonium?
Amino acids. NH4 is then converted to urea in the liver for excretion in the urine or feces
What is the preferred fuel of the liver?
Fatty acids, glucose and amino acids
What is the preferred fuel of adipose tissue?
What is the preferred fuel of skeletal muscle?
At rest: fatty acids
During exercise: glucose
What is the preferred fuel of heart muscles?
What is the preferred fuel of the brain?
Fed State: glucose
Starvation: ketone bodies/glucose
Why is maintenance of a normal range of blood glucose so important?
The brain has an absolute need for glucose. Without it, nerve cells die in a very short time period.
In the fasted state, what provides most of the ATP needed for gluconeogenesis?
Fatty Acid oxidation
In a fasting state, where does the increased blood levels of fatty acid come from?
Low blood insulin levels cause the activation of lipolysis in adipose tissue.
When does the brain start to rely on ketone bodies?
During periods of extreme starvation, the liver completely oxidizes the acetyl-CoA formed from fatty acids into ketone bodies in the liver's mitochondria. As blood ketone levels rise, the brain upregulates it's transporters and begins to use ketone bodies for fuel.
What are the five major dietary carbohydrates?
Amylose, Sucrose, Lactose, Fructose, Glucose
What sort of foods is amylose found in?
Potatoes, rice, corn, bread
What sort of food is sucrose found in?
Table sugar, desserts
What sort of food is lactose found in?
Milk, milk products
What sort of food is fructose found in?
What sort of food is glucose found in?
Fruit, honey, grapes
What is starch?
Polymer composed entirely of glucose
What hormone is responsible for the regulation of glucose metabolism?
Insulin. It's major function is to maintain low blood glucose levels. It promotes glycolysis on a long-term basis as well as glycogen synthesis
What hormone causes the liver to release glucose into the blood?
What is glycogenolysis?
The breakdown of glycogen to glucose-1-phosphate and glucose in the liver and in the muscles by the enzyme glycogen phosphorylase
What is the last step in glycolysis?
The generation of pyruvate.
What is gluconeogenesis?
The generation of glucose from non-carbohydrate carbon sources such as pyruvate, lactate, glycerol and glucogenic amino acids
Which uses more glucose throughout the day, the brain or skeletal muscles?
The brain! The brain uses around 120- grams of glucose per day, whereas muscle tissue only uses 40 grams.
What are the two pathways for dietary glucose during the fed state?
The fed state results in glucose storage and energy production. Therefore, dietary glucose can either be converted into glycogen by glycogenesis or can be converted into pyruvate/lactate by glycolysis
In the well fed state, how does the liver handle glucose?
In a well fed state the liver uses glucose for fuel, and does NOT engage in gluconeogensis
What allows glucose to be taken up from the blood and converted into either energy or glycogen during the fed state?
Beta-cells of the endocrine pancreas!
beta-cells are very responsive to the influx of glucose and amino acids, causing it to release INSULIN
What is the hormonal response to falling glucose levels in the blood during starvation state?
Alpha-cells of the endocrine pancreas release glucagon.
The adrenal medulla also releases epinephrine
Where are glucagon receptors found?
Only in the liver
What happens to glycogen in the liver during times of starvation?
Glycogen is actively degraded in the liver. Once glucose-6-phosphate is generated, the liver will not use it, but rather will convert it to glucose
Why can't red blood cells use amino acid or fatty acid metabolism for energy?
They lack mitochondria. These processes only take place in the mitochondria
What is the only source of energy in red blood cells?
Glucose --> glycolysis
Describe the role of glucose in the brain
The brain has an absolute requirement for glucose. Although there is a very small glycogen reserve in the brain, and under extreme starvation it can utilize ketone bodies for energy production, it always requires some glucose for normal function and neuronal health
Other than the liver, what tissues have major glycogen storage?
Skeletal muscle/the heart
Can skeletal muscle provide some glucose into the bloodstream during times of starvation?
No- muscle cells cannot mobilize glycogen or glucose into circulation. Only the liver is responsible/capable of maintaining proper blood glucose levels during starvation
What is the fate of in adipose tissue?
Adipose tissues convert excess glucose into fat (glucose --> acetyl CoA --> fat)
Discuss ATP production in adipose tissues
There is no TCA cycle in adipose tissue cells, therefore there is very little ATP production (outside of the ATP generated during glycolysis). All excess energy is stored as fat
What are the two distinct groups of transporters used to transport hexoses (glucose, galactose and fructose) across cellular membranes?
GLUT transporters- facilitated diffusion down a concentration gradient
SGLT transporters- sodium dependent symporters that transport hexoses against their concentration gradient
Is GLUT2 insulin dependent or independent?
GLUT2 is insulin independent.
Is GLUT4 insulin dependent or independent?
GLUT4 is insulin dependent.
Discuss the differences in the location of GLUT2 and GLUT4 hexose transporters
GLUT2: low affinity high capacity transport in the LIVER, also found in the kidney and intestines. The transporter is bidirectional. GLUT2 transports glucose out of the intestine, into the bloodstream, and into the liver (which sees a very high concentration of glucose)
GLUT4: found in muscle, heart and adipocytes. It has a higher affinity for glucose and sucks up glucose after we have eaten. It is not active during the fasting state (because insulin levels are low)
Discuss how blood glucose concentration affects how where glucose is taken up.
GLUT transporters have different affinities for glucose. The lower affinity glucose transporters (GLUT1 and GLUT3) have high affinities and will take up glucose quickly at low concentrations, but consequently max out at low concentrations.
GLUT2 has a low affinity for glucose, and therefore only begins to take up glucose at higher concentrations in the blood. GLUT2 transporters will not max out.
GLUT4 has a relatively low affinity for glucose as compared to GLUT2. Therefore, GLUT4 will max out taking up glucose into the muscles, heart and adipocytes at lower concentrations. At high concentrations (such as after eating), GLUT2 transporters will begin to take glucose into the liver.
What are the three enzymes of glycolysis that regulate irreversible steps?
Hexokinase/glucokinase- glucose to G6P
PFK-1- Fructose 6-phosphate to Fructose-1,6-bisphosphate
Pyruvate kinase- PEP to pyruvate
What are three ways that methods for regulation of the key enzymes in glycolysis?
1) allosteric regulation
2) covalent modification
3) Regulation of the amounts/synthesis of the enzymes
What is the net ATP generated from one molecule of glucose during glycolysis?
Produces 4 ATP, uses 2 ATP
Net= 2 ATP
Where in the cell does glycolysis take place?
In the cytoplasm- therefore it is active in all cell types (mitochondria is not required)
Other than ATP, what other form of energy is produced during glycolysis?
At what state is glucose trapped in the cell?
When glucose is phosphorylated to become glucose-6-phosphate, it is trapped in the cell
Phosphorylation of an enzyme occurs on what functional group?
Contrast the location of hexokinase vs. glucokinase.
Hexokinase is found in all cells
Glucokinase is present only in the liver and pancreas
Contrast the inhibition of hexokinase vs glucokinase
Hexokinase: allosterically inhibited by G6P
Glucokinase: inactivated by translocation to the nucleus (promoted by fructose 6 phosphate)
Contrast the stimulation of hexokinase vs glucokinase
Hexokinase is constitutively active
Glucokinase activity is increased by insulin (which is released in response to glucose: higher glucose leads to higher glucokinase activity)
Contrast the saturation of hexokinase vs glucokinase
Hexokinase: saturated at low concentrations of glucose
Glucokinase: saturated at high concentrations of glucose--> not saturated at normal physiological concentrations
Discuss the primary role of hexokinase vs. glucokinase
Hexokinase, present in all tissues, generates energy through the initiation of glycolysis only when energy is needed.
Glucokinase is activated IN THE LIVER (and pancreas) only when glucose levels are very high, where it can begin to process glucose into acetyl CoA for the purposes of making fatty acid and glycogen
What is the reaction catalyzed by phosphofructokinase 1?
Fructose-6-Phosphate --> Fructose 1,6-Phosphate
Generally, what are the allosteric regulators of hepatic PFK-1?
Activation: molecules that are indicative of low energy in the cell (AMP, ADP and Fructose-2-6-bisphosphate)
Inactivation: molecules that indicate high energy in the cell (ATP and citrate)
What is the major physiologic activator of hepatic PFK-1?
How does Fructose-2-6-bisphosphate act as a regulator of PFK-1?
Fructose-6-phosphate is phosphorylated to Fructose-2-6-bisphosphate by phosphofructokinase-2. F-2-6-BP is formed when blood glucose (and insulin) are high (signaling sufficient substrates for glycolysis); it is not formed when blood glucose is low.
What hormones regulate the formation of fructose-2-6-bisphosphate in the liver?
Epinephrine and glucagon inhibit the formation (they are indicative of low blood glucose), and
How does PKA affect PFK-2?
PKA phosphorylates and inhibits PFK-2.
PKA is high in starvation. PKA therefore inhibits PFK-2 and so fructose-6-phosphate stays as F6P and can be used to generate energy
What does it mean that PFK-2 is a bifunctional enzyme?
PFK-2 has both a kinase AND a phosphatase domain. Phosphorylation of one of the domains inactivates it, and the other domain is active.
Why does citrate inhibit PFK-1?
Citrate is an intermediate of the citric acid cycle. High citrate levels indicate high ATP levels in the cell, and therefore glycolysis is not necessary.
How does epinephrine affect glycolysis in skeletal muscle vs hepatic tissue?
Epinephrine stimulates glycolysis in skeletal muscle, but inhibits glycolysis in the liver
Where are glucagon receptors found?
How does epinephrine affect PFK-2 and glycolysis in skeletal muscle and the heart?
Epinephrine activates PFK-2 (forms more fructose 2-6 bisphosphate) and therefore activates glycolysis.
What reaction is catalyzed by pyruvate kinase?
PEP --> pyruvate
What allosterically stimulates pyruvate kinase?
Fructose 1,6-bisphosphate (a previous intermediate of glycolysis)
What allosterically inhibits pyruvate kinase?
ATP: indicative of a high energy state
Alanine: indicative of fasting mode and serves as a precursor for gluconeogenesis.
How does glucagon and epinephrine affect hepatic pyruvate kinase?
Glucagon and epinephrine INHIBIT hepatic pyruvate kinase. It acts through cAMP and PKA to cause the phosphorylation and therefore inactivation.
When is glucagon released?
Glucagon is released from pancreatic alpha cells in times of low blood glucose. Because glucagon receptors are only in the liver, all actions are limited to the liver
When is epinephrine released?
Epinephrine is released from the adrenal medulla. Epinephrine binds to most cell types, and increases glycolysis. Glycolysis is inhibited in the liver so that glucose can be preserved for tissue that have a fuel preference or high demand for glucose.
Glucagon/epinephrine inhibit hepatic glycolysis by indirectly inhibiting _______ and directly inhibiting _____.
PFK1 , pyruvate kinase
How does glucagons /epinephrine affect the synthesis of the three irreversible enzymes of glycolysis?
In the liver, glucagon and epinephrine decrease the synthesis of the three irreversible enzymes of glycolysis (Hexokinase, PFK-1 and pyruvate kinase)
Lactate Dehydrogenase is important in the regeneration of what important molecule?
NAD+ (through the conversion of pyruvate to lactate)
What enzyme catalyzes the reaction pyruvate --> acetyl CoA?
What are the three enzymes that complex to form pyruvate dehydrogenase?
E1, E2, E3
How is PDH regulated?
Allosterically- negative feedback from Acetyl CoA and NADH, the products of the reaction
Covalently- the end products of the PDH reaction cause PDH to become phosphorylated, which inhibits its activity
What co-factors are required for proper PDH function?
Vitamins; (thiamine, pantothenate, riboflavin and niacin)
What is the net generation of ATP from the TCA cycle?
What steps of glucose metabolism require O2?
PDH and the TCA cycle require O2.
Glycolysis is O2 independent
How are dietary galactose and fructose utilized for energy?
They must first be converted to a glycolytic intermediate.
What deficiency is linked to cataracts and what is the problem?
Galactosemia (increased blood galactose): the deficiency of either galactokinase or galactose 1-phosphate uridyltransferase- the enzymes necessary for converting galactose to glucose-6-phosphate