Metabolism (Exam 1) Flashcards
Carb absorption, metabolism, hormonal regulation, Glycogen production, sugar and alcohol
Insulin binds to what type of receptors?
Tyrosine kinase
Intertissue integration is required for metabolic homeostasis. How is metabolic homeostasis achieved?
- The concentration of nutrients in the blood affect the rate at which they are stored and utilized
- Hormones carry messages to tissues
- CNS sends neuronal signals to control tissue metabolism
What is the goal of glucagon?
Glucagon is the major fuel mobilization hormone.
What is the goal of insulin?
Insulin is the major anabolic hormone for the body.
What happens to insulin levels when you eat a meal? What does insulin do to cell processes after you eat a meal?
Insulin levels rise and glucose enters cells. Fuel stores and growth in cells are increased.
What happens to glucagon a few hours after eating a meal?
Glucagon levels rise. The goal is to maintain fuel levels in the blood. Stored fueled is now utilized to produce ATP.
Where is insulin secreted from?
Insulin is secreted from the beta-cells of the islets within the pancreas.
Where is glucagon secreted from?
Glucagon is secreted from the alpha-cells of the islets in the pancreas.
Islets of the pancreas are very close to the vasculature. Why is this important?
Islets being close to the vasculature allows the cells to monitor the blood glucose levels and secrete insulin or glucagon accordingly.
What are the main functions of insulin?
- Promotes fuel storage after a meal
- Promotes growth
What are the 3 major metabolic pathways affected by insulin secretion?
- Stimulates glucose storage as glycogen in liver and muscle
- Stimulates fatty acid synthesis and storage in adipose tissue
- Stimulates amino acid uptake and protein synthesis
What are the main functions of glucagon?
- Mobilizes fuels
- Maintain blood glucose levels during fasting
What are the 2 major metabolic pathways affected by glucagon secretion?
- Activates gluconeogenesis and glycogenolysis in the liver during fasting
- Activates fatty acid release from adipose tissue
What is another hormone discussed that mobilizes fuels during acute stress?
Epinephrine
What are the two counterregulatory hormones of insulin?
Epinephrine and cortisol. As hypoglycemia is a stress signal, it stimulates the release of EPI and cortisol from the hypothalamic regulatory center (central HPA axis).
Where are the 3 locations where insulin acts?
Liver
Skeletal Muscle
Adipose tissue
What are the 2 locations where glucagon acts?
Liver
Adipose tissue
(NOT MUSCLE)
What is the process of the hormone insulin being made?
- Synthesized as a pre-hormone in the nucleus
- Moves to ER and is converted to preproinsulin
- Moves to golgi and the C peptide is cleaved
- Leaves golgi as active insulin and stored in vesicles with zinc.
What is the characteristics of the bonds within biologically active insulin?
The A and B chains are linked together by two interchain disulfide bonds.
What is the initiating step for insulin release from beta-cells?
Glucose levels have increased and enter the beta cells through GLUT2 where insulin is made and stored. This activates the release of insulin to the rest of the body.
What is the step-by-step breakdown of insulin release from beta-cells in the pancreas?
- Beta-cells detect glucose in the blood
- Glucose is taken up via GLUT2 transporters in beta cells
- Beta cells increase glycolysis, TCA cycle, oxidative phosphorylation, and then ATP
- Rise in ATP levels inhibits ATP-dependent K+ channels. This depolarizes the membrane
- Depolarization activates voltage-gated Ca2+ channels
- Increased intracellular calcium leads to vesicle fusion with membrane releasing insulin into the blood
Why would epinephrine reduce insulin secretion?
Epinephrine is the fight-or-flight hormone while insulin is the storage hormone. With EPI release, you want release and utilization of energy and not storage.
Explain the steps of insulin receptor cell signalling in terms of the tyrosine kinase receptor and GLUT4.
- Insulin binds to alpha subunits of tyrosine kinase receptors
- Insulin receptors dimerize
- Beta subunits of the tyrosine kinase receptor extend through the membrane and autophosphorylate each other
- Downstream signalling activates P13K which activates AKT
- This leads to the translocation of GLUT4 into the plasma membrane
What is the tissue response to insulin binding?
- Stimulates glucose and amino acid uptake into the cells
- Reverses glucagon-stimulated phosphorylation
- Initiates phosphorylation of enzymes
- Induces and suppresses enzyme synthesis
- Acts as a growth factor
What is the process of the hormone glucagon being made?
- Glucagon is synthesized in the alpha-cells of the pancreas. Initially produced in the rough ER
- Converted to proglucagon in the ER lumen
- Cleavage at certain sites produces the biologically active glucagon
What is the half-life of glucagon?
The half life is glucagon is 3-5 minutes as rapid regulation is needed.
What macronutrients stimulates the release of glucagon?
Amino acids
Does epinephrine increase or decrease glucagon secretion?
Epinephrine increases glucagon secretion in order to mobilize fuel stores.
Similar to another question asked, what are the 4 exact names of the metabolic pathways that insulin activates?
Glycogen synthesis
Fatty acid synthesis
Triglyceride synthesis
Liver glycolysis
Similar to another question asked, what are the exact names of the metabolic pathways that glucagon activates?
Glycogenolysis
Gluconeogenesis
Lipolysis
DECREASES LIVER GLYCOLYSIS
What happens when glucagon binds to its receptor, GPCR, in terms of cellular molecules?
- Glucagon binds to GPCR
- This activates cAMP signalling
- cAMP activates PKA
- PKA activates PPK
- Through several downstream signalling molecules, glycogen is broken down into glucose-1-phosphate to make glucose (liver)
What are the 5 major principles of molecule signalling regarding hormones?
- Specificity- action given by receptor expression
- Amplification- signalling cascade
- Termination- rapid stopping
- Integration- of cellular response
- Augmentation/ Antagonism of signal
Epinephrine is a potent stimulator of the _____________ receptors.
Adrenergic (alpha and beta)
What type of adrenergic receptor in present in the liver and skeletal muscle?
Beta2 Adrenergic receptors
When epinephrine binds to B2 on the liver and muscle, what does it do?
Epinephrine binding to beta2 on liver and muscle mobilizes the use of glucose as fuel.
How do adrenergic beta receptors signal?
Beta adrenergic receptors signal using stimulatory GPCR to activate adenylate cyclase and PKA.
(PKA stimulation leads to the breakdown of glycogen called glycogenolysis)
What is blood glucose for someone is who prediabetic?
Fasting glucose levels between 100 and 125 mg/dL
What are the two forms of plant starches in the diet?
Amylose and Amylopectin
What is the bond type that holds amylose together?
Glucose residues linked by alpha-1,4-glycosidic bonds
What is the bind type that holds amylopectin together?
Branched glucose residues are linked by alpha-1,4-glycosidic bonds connected by alpha-1,6-glycosidic bonds
What bond type holds together the disaccharide, lactose (galactose and glucose)?
beta-1,4-glycosidic bonds
What bond type holds together the disaccharide, sucrose (glucose and fructose)?
alpha-1,2-glycosidic bonds
What is the group name for the enzymes that hydrolyze glycosidic bonds?
Glycosidases
What is the first glycosidase encountered during digestion?
salivary alpha-amylase
What is pancreatic alpha-amylase?
This is the second glycosidase encountered. It is released from the pancreas along with bicarbonate into the stomach. It hydrolyzes alpha-1,4 bonds into random length polysaccharides.
Does pancreatic alpha-amylase have any action on alpha-1,6-glycosidic bonds?
No! It only has action on the alpha-1,4-glycosidic bonds.
What are the two enzymes in the small intestine that continue to break down carbohydrates?
Small intestinal disaccharidases and glucoamylase.
What is the function of small intestinal disaccharidases?
These cleave disaccharides in the small intestine.
What is the function of glucoamylase in the small intestine?
Glucoamylase is an alpha-1,4-exoglycosidase meaning that is cleaves the end of the sugar.
What is the function of the sucrase-isomaltase enzyme?
Sucrase-Isomaltase hydrolyzes 100% of the remaining alpha-1,6-glycosidic bonds.
_______________ accounts for 100% of the ability to hydrolyze sucrose.
Sucrase-isomaltase
What is the enzyme trehalase?
This enzyme hydrolyzes glycosidic bonds found in trehalose which is found in mushrooms, fungi, and insects.
What brush-border enzyme hydrolyzes the bond between glucose and galactose in lactose?
Lactase. Lactase is a beta-glycosidase complex. It cleaves the beta-1,4 bond.
What are the two transport mechanisms in which glucose crosses the intestinal epithelial cells?
- Facilitated diffusion
- Na+ Dependent facilitated transport
Explain the process of Na+ dependent transport and the Na+, K+-ATPase in the transport of glucose across the intestinal epithelial cells.
The high Na+ gradient in the lumen of the GIT drives glucose and galactose into the epithelial cells. The Na+, K+-ATPase kicks out 3 Na+, and brings in 2 K+ to maintain concentration gradient for the extracellular Na+. The ATPase hydrolyzes ATP to ADP and Pi to do this.
What are the characteristics of facilitated glucose transport?
They do not bind Na+. They move glucose from a high to low concentration. Includes GLUT1-5.
Where are GLUT2 transporters located?
GLUT2 transporters are located in the liver, kidney, pancreatic B-cells, and serosal surface of intestinal mucosa.
Where are GLUT3 transporters located?
Neurons of the brain
Where are GLUT4 transporters located?
Adipose tissue, skeletal muscle, and heart muscle.
What type of GLUT transporters transports fructose in the intestinal epithelium?
GLUT5
Once glucose has made it way through the intestinal epithelium, what is happening?
The glucose is now in the blood and signals insulin release in the pancreas
What type of receptors are insulin receptors?
Tyrosine kinase
How is glucose transported into the brain?
- Glucose passes through GLUT1 transporters in the endothelial cell membrane in the brain (rate-limiting)
- Once inside brain, neurons use GLUT3 to transport glucose from CSF to interior of the cell (fast)
Why does the difference in transporter between the PNS and CNS matter?
It matters because in the brain, the maximal rate of transport is similar to glucose utilization.
What is the name of the enzyme that is the primary mechanism by which starch is metabolized?
Amylase
Glycogen is composed of _____________ linked by glycosidic bonds.
Glucosyl units
__________ is the intermediate in glycogen formation.
UDP-glucose
Why is glycogen branched?
Glycogen is branched so that the body can store as much as possible. The branched structure also allows for rapid formation and degradation
What is the only non-glucosyl unit within glycogen?
Glycogenin. It is the initial residue in glycogen formation.
How is glycogen utilized in the skeletal muscle?
Glycogen is broken down to G1P which is converted to G6P via phosphoglucomutase. G6P enters glycolysis to provide energy via aerobic and anaerobic processes because it does not contain glucose-6-phosphate like the liver. It can generate ATP and lactate. Lactate is shuttled to the liver.
Glycogenolysis and gluconeogenesis are activated ___________ in the liver due to the hormone _________.
Together
Glucagon
Glycogen synthesis and breakdown are very similar. However, the synthesis pathway uses __________ phosphate bond for energy.
UTP
What is the regulated enzyme of glycogen synthesis?
Glycogen synthase
What molecules donates glycosyl residues to the reducing end of glycogen in glycogen synthesis?
UDP-glucose
What enzyme in glycogen synthesis links alpha-1,4-glycosidic bonds?
Glycogen synthase
What enzyme in glycogen synthesis creates branches on glycogen by forming alpha-1,6-glycosidic bonds?
Branching enzyme
What converts G1P to UDP-glucose in glycogen synthesis?
UDP-glucose pyrophosphorylase uses UTP to convert G1P to UDP-Glucose.
What two enzymes convert UDP-Glucose to glycogen through a long process?
Glycogen synthase and branching enzyme
What are the two enzymes that degrade glycogen?
Glycogen phosphorylase and debrancher enzyme.
What is the function of alpha-1,6-glucosidase enzyme in the breakdown of glycogen?
It cleaves the glucose residue linked at the alpha-1,6-bond which is released as one free glucose.
Every branch point on glycogen yields at least ______ glucose and _________ to _______ G1P residues.
1
7-9
Explain glucagon binding and downstream molecules it activates to breakdown glycogen?
Glucagon binds to GPCR
GTP stimulates adenylate cyclase
Adenylate cyclase converts ATP to Cyclic AMP
Cyclic AMP activates Protein Kinase A
Protein Kinase A activates Phosphorylase Kinase and deactivates glycogen synthase alpha to glycogen synthase beta.
Phosphorylase Kinase activates glycogen phosphorylase B to glycogen phosphorylase A. Phosphorylase A activates glycogen breakdown
What two molecules regulate glycogen breakdown in the muscle?
AMP and Ca2+
Why is glycogenolysis much more rapid than gluconeogenesis in the liver when activated?
Glycogen is sitting in the liver and can be broken down rapidly while non-carbohydrate precursors need to be recruited for gluconeogenesis.
Are glycogen synthesis and degradation regulated simulataneously?
Yes
Does PKA activation make glycogen phosphorylase kinase active or inactive?
PKA activation makes glycogen phosphorylase kinase active. Active phosphorylase kinase activates glycogen phosphorylase A therefore increasing glycogen breakdown.
Does PKA activation activate or inhibit glycogen synthase?
PKA activation inactivates glycogen synthase. Inactive glycogen synthase has a phosphate group attached to it and prevents glycogen storage.
Does protein phosphatase-1 activate or inactivate glycogen synthase?
Protein phosphatase-1 activates glycogen synthase by removing a phosphate group. This makes sense at PP1 is inhibited during fasting so it would be activated during the fed state allowing glucose to be stored as glycogen.
Does protein phosphatase-1 activate or inactivate phosphorylase kinase?
PP1 inactivates phosphorylase kinase by removing a phosphate group from it. This makes sense because PP1 is inhibited during fasting allowing phosphorylase kinase to stay active and activate glycogen phosphorylase A inducing glycogen breakdown to glucose.
Muscle lack the enzyme ___________ so it cannot restore blood glucose levels like the liver can.
Glucose-6-phosphatase
What two molecules regulate glyconeolysis in the muscle?
AMP and Ca2+. These are low energy indicators. AMP is produced from the degradation of ATP during muscle contraction. Ca2+ is released from sarcoplasmic reticulum due to neuronal impulses and it binds to calmodulin which activates phosphorylase kinase which activates glycogen phosphorylase B to A.
AMP is an activator of glycogen phosphorylase in the __________ but not in the liver.
muscle
Glycogen is made up of what types of glycosidic bonds?
Alpha-1,4 and alpha-1,6
The initial residue required for glycogen formation is ________.
Glycogenin
The biochemical breakdown of glycogen is called _________.
Glycogenolysis
Two enzymes required for glycogen breakdown are ___________ and ____________.
Glycogen phosphorylase and debrancher enzyme
Through what transporter does fructose enter intestinal epithelial cells?
GLUT5
What is the first step of fructose metabolism?
Fructose is converted to Fructose-1-phosphate via fructokinase. This step uses an ATP.
What is the 2nd step of fructose metabolism?
Fructose-1-phosphate is converted to glyceraldehyde via Aldolase B. Dihydroxyacetone-phosphate (DHAP) is cleaved off and enters glycolysis.
What is the 3rd step of fructose metabolism?
Glyceraldehyde is converted to glyceraldehyde-3-phosphate via triose kinase. G3P then enters glycolysis.
Where does fructose metabolism occur?
Primarily the liver
What is Polyol Pathways?
This is the conversion of glucose to fructose.
What are the steps in the polyol pathway?
Glucose ——> sorbitol via aldose reductase (step uses an NADPH)
Sorbitol ———> fructose via sorbitol dehydrogenase (produces an NADH)
What is a pathophysiology that occurs due to increased blood glucose levels due to the generation of sorbitol (alcohol sugar)?
Ocular glaucoma
What are the steps of galactose metabolism in the liver?
- Galactose + ATP —–> Galactose-1-phosphate + ADP via Galactokinase
- Galactose-1-phosphate + UDP-glucose —-> UDP-galactose + glucose-1-phosphate (G1P enter glycolysis)
- UDP-galactose —-> UDP-glucose via UDP-glucose epimerase
Galactose metabolism is _______ when we are younger and ________ when we are older.
HIGHER
SLOWER
This is due to galactose being the monosaccharide of lactose which is consumed in diary products like milk.
What is generated in the Pentose Phosphate Pathway?
The PPP generate NADPH and ribose-5-phosphate
What are the two phases of the pentose phosphate pathway?
Oxidative phase and nonoxidative phase
What is the 1st step of the pentose phosphate pathway?
Glucose-6-phosphate ——> 6-phosphogluconolactone via glucose-6-phosphate dehydrogenase
Makes an NaDPH
What is the 2nd step of the pentose phosphate pathway?
6-phosphogluconolactone ——> 6-phosphogluconate via gluconolactonase
What is the 3rd step of the pentose phosphate pathway?
6-phosphogluconate ——-> Ribulose-5-phosphate via 6-phosphogluconate dehydrogenase
What are the two fates of ribulose-5-phosphate once it is made in the oxidative phase of the pentose phosphate pathway?
It can become Ribose-5-phosphate and make nucleotides or it can become Xylulose-5-phosphate
What determines the directionality of the pentose phosphate pathway?
Energy needs of the cell.
If the cells is dividing, it needs nucleotides or is undergoing transcription and translation, ribose-5-phopshate will be made. It the cell is not doing those things, it will go towards converting to glucose.
How is NADPH used to combat reactive oxygen species?
NADPH is used in glutathione conjugation to convert hydrogen peroxide (H202) to 2 molecules of water.
Entry of Glucose-6-phopshate into the pentose phosphate pathways in regulated by _______ levels.
NADPH
If the need of the cell is only NADPH, what is the direction of the pentose phosphate pathway?
Oxidative rxns produce NADPH. Non-Oxidative rxns convert ribulose-5-phosphate to glucose-6-phopshate to make more NADPH.
If the energy needs of the cell are NADPH and Ribose-5-phosphate, what is the direction of the pentose phosphate pathway?
Oxidative rxns produce NADPH and ribuluse-5-phosphate. The isomerase rxn will convert ribulose-5-phosphate to ribose-5-phosphate.
If the energy needs of the cell are only ribose-5-phosphate, what is the direction of the phosphate pentose pathway?
Only the nonoxidative reactions. High NADPH levels inhibit glucose-6-phosphate dehydrogenase, so transketolase and transaldolase will be used to convert fructose-6-phosphate to glyceraldehyde-3-phosphate and ribose-5-phosphate.
If the energy needs of the cell are NADPH and pyruvate, what direction does the pentose phosphate pathway go?
Both oxidative and nonoxidative rxns are used. Oxidative rxns will generate NADPH and ribulose-5-phopshate. Non-oxidative will convert ribulose-5-phosphate to fructose-6-phosphate and glyceraldehyde-3-phopshate and glycolysis will convert them to pyruvate.
What are the 3 major enzymes of ethanol metabolism?
Alcohol dehydrogenase
Acetaldehyde dehydrogenase
Microsomal ethanol oxidizing system (MEOS)
What is the metabolite of alcohol that causes nausea and vomiting?
Acetaldehyde
What are the steps of ethanol metabolism?
Ethanol ———> acetaldehyde via alcohol dehydrogenase. NADH produced
Acetaldehyde ——–> acetate via acetaldehyde dehydrogenase. NADH produced
What is the drug disulfiram (antabuse)?
Disulfiram is an acetaldehyde dehydrogenase inhibitor.
What is acetate converted to?
Acetate is converted to Acetyl CoA in the liver, muscle and other tissues to enter the TCA cycle.
When is the MEOS or CYP2E1 system activated for alcohol metabolism?
This system is activated during to chronic drinking.
How much energy is produced from one mole of ethanol?
With alcohol and acetaldehyde dehydrogenase, 13 ATP/ mole of ethanol is made.
With the CYP2E1 system, 8 ATP/ mole of ethanol is made.
What is the main enzyme in the MEOS?
CYP2E1
What are the acute effects of ethanol metabolism?
Increased NADH/NAD+ ratio leading to inhibition of FA oxidation therefore they are reesterified into triacylglycerols and incorporated into VLDL.
What are the chronic effects of ethanol metabolism?
Long-term, there is so much NADH that other metabolism processes begin to backup. Acetyl CoA becomes ketone bodies which leads to ketoacidosis due to OAA being pushed towards malate and therefore no citrate synthesis. Hypoglycemia can also occur due to the use of non-carb precursors to convert pyruvate to lactate. Lactate can produce ethanol-induced lactic acidosis.
In a general sense, what are the results of chronic ethanol use?
Lactic acidosis, ketoacidosis, and hypoglycemia due to very high NADH/NAD+ ratio.
What is the only enzyme that can cleave fructose-1-phosphate?
Aldolase B
T or F: Galactose metabolism requires an initial energy investment.
True
What phase of the pentose phosphate pathway is responsible for the majority of cellular NADPH?
Oxidative phase
What are the 3 major dietary carbohydrates?
Starch, lactose, and sucrose
________ enzyme digests starch.
Amylase
Sucrose is a disaccharide of _______ and ________.
Glucose and fructose
____________ are enzymes that hydrolyze glycosidic bonds.
Glycosidases
Which of the following enzymes has activity at alpha-1,6-glycosidic bonds?
A. Amylose
B. Glucoamylase
C. Sucrase-isomaltase complex
D. All of the above
C. Sucrase-isomaltase complex
Amylase breaks a-1,4 bonds and glucoamylase is an alpha-1,4-exoglucoaside and cleaves the end sugar molecules
What type of bond is present in amylose?
Alpha-1,4
What type of bond is present in Lactose?
Beta-1,4
What type of bond is present in sucrose?
Alpha-1,2
What type of bond is present in amylopectin?
alpha-1,6 bonds
alpha-1,4 also present
B-glycosidase complex catalyzes which enzyme?
A. Lactase
B. Amylase
C. Sucrase
D. Glucoamylase
A. Lactase
T or F: Glucose can be symported with Na+.
True. Glucose and Galactose are transported by Na+-glucose cotransporters on the luminal side of absorptive cells.
T or F: GLUT1 is the glucose transported found in the liver and pancreas.
False. GLUT2 in found in the liver and pancreas