Valencik Carb Metabolism Flashcards
What are the 4 things that pyruvate can turn into & how?
- Lactate; reduction
- acetyl CoA; oxidative decarboxylation
- oxaloacetate; carboxylation
- alanine; transamination
Pyruvate dehydrogenase only works under ___ conditions. Describe this step in detail.
aerobic conditions.
Pyruvate–>Acetyl CoA
requires NAD+; gives off NADH
Also produces CO2
Where does pyruvate dehydrogenase do its thing?
in the mitochondrial matrix. The pyruvate is transported across the membrane.
Pyruvate dehydrogenase is a ____ enzyme that causes a ____ reaction.
alpha ketoacid dehydrogenase
irreversible reaction
Aside from pyruvate dehydrogenase, what is another example of alpha ketoacid dehydrogenase?
alpha ketoglutarate dehdyrogenase
Oxidative decarboxylation is an ______ reaction.
irreversible
What are the 3 catalytic enzymes that make up the pyruvate dehydrogenase complex?
E1: on the outside…pyruvate dehydrogenase
E2: in the core…DLTA: dihydrolipoyl transacetylase
E3: in the core…DLDH: dihydrolipoyl dehdyrogenase
What are the 5 coenzymes that make up the pyruvate dehydrogenase complex?
TPP: thiamine pyrophosphate CoA: coenzyme A NAD+ FAD+ Lipoamide
What are the vitamins that are required for the coenzymes of pyruvate dehydrogenase to work?
TPP-- requires thiamine (B1) CoA--requires panthothenic acid (B5) NAD--requires niacin (B3) FAD--requires riboflavin (B2) Lipoamide--doesn't require anything
Beri Beri is caused by a deficiency of what? What 3 things build up in the body as a result? This can impair CNS function etc.
thiamine deficiency
pyruvate, lactate, alanine (after you eat lots of carbs)
**body can’t make acetyl CoA very easily
TPP contains what ring? It carries what 2 things? It is bound noncovalently to what?
thiazolium
pyruvate
hydroxyethyl group
apoprotein
Lipoamide is required for which enzyme that is a part of the pyruvate dehydrogenase complex?
required for E2: the outer edge: a part of DLTA
How is the lipoate attached to the E2 enzyme?
bound covalently w/ an amide linkage to the lysine
synthesized directly onto the E2 enzyme to form the lipoyl domain…never free
T/F There is free lipoic acid that is a part of the E2 enzyme.
False. B/c the lipoic component of the E2 enzyme is synthesized directly on there–>it is not ever freely hanging around.
What does lipoic acid do in the pyruvate dehdyrogenase complex?
participates in redox & carries an acetyl group
What does coenzyme A help activate? What complex is this a part of?
DLTA/E2
pyruvate dehydrogenase complex
What vitamin does coenzyme A require?
Vitamin B5; pantothenic acid
What are 2 things that are required for activation of DLDH? dihydrolipoyl dehydrogenase
NAD+ & FAD
Talking NAD+ here.... What vitamin does it require to be active? What enzyme component does it activate? Of what complex? What is its function?
VItamin B3; Niacin
DLDH
Pyruvate Dehydrogenase Complex
Hydride Transfers
With NAD & FAD…unlike CoA…??? Talk about a carbon.
The number 3 carbon in adenosine is not phosphorylated in NAD & FAD.
talking FAD here... What vitamin is required to make it active? What enzyme component does it activate? Of what complex? What is its function?
Vitamin B2; Riboflavin FAD is the active form of riboflavin DLDH Pyruvate Dehydrogenase Complex Electron transfers
Aside from the enzymes we have been talking about (the 3 special ones) what are 2 other enzymes that are attached to the pyruvate dehydrogenase complex for the purpose of their regulation?
PDH kinase (4 isoforms) PDH phosphatase (2 isoforms)
What is the purpose of PDH Kinase & PDH Phosphatase?
They regulate the activity of the pyruvate dehydrogenase complex. When the kinase does its thing & phosphorylates the complex–>it is inactive. When the phosphatase does its things & dephosphorylates it, it is active.
Called reversible covalent phosphorylation.
Overall: You start with pyruvate & end up with ____. You use the ____ _____ complex. You add in what 5 things? You get out what 3 things?
acetyl CoA pyruvate dehydrogenase complex NAD FAD TPP Lipoamide CoA You get: acetyl CoA (obviously) & NADH & CO2!!!
Talking from glucose to the TCA cycle…what requires O2 & what doesn’t? And where does everything happen?
Glycolysis doesn’t require O2.
Conversion into Acetyl CoA & TCA cycle both happen in the cytosol of the mitochondrion. They both require O2.
What nutrients turn into acetyl CoA eventuallY?
All the major ones!!! Carbs Fats Proteins Alcohol
What does acetyl CoA turn into?
TCA or... Acetylated Products Cholesterol Ketone Bodies Fatty Acids
So…what is Danielle’s amazing phrase for TCA & what does each stand for?
Can: Citrate I: Isocitrate Keep: alpha ketoglutarate Selling: Succinyl CoA Sex: Succinate For: Fumarate Money: Malate Officer: Oxaloacetate
Show the math. 1 glucose molecule…how much energy from TCA??
1 glucose 2 pyruvate 2 acetyl CoA 4 CO2 6 NADH=18 ATP 2 FADH2=4 ATP 2 GTP=2ATP Overall: 1 glucose (from TCA) = 24 ATP
What is the efficiency of glucose oxidation?
40%
How does glucose travel in the blood?
attached to albumin
What are the 3 sources of blood glucose?
food
glycogen degradation
gluconeogenesis
How long is food good for as a source of blood glucose?
a few hours after a meal
The _____ stores ____ of glycogen & supplies it for up to a ____ period of time.
liver stores 100 g of glycogen & supplies it for up to 24 hours
How much energy is consumed in degrading glycogen to put it into the blood? Is this process slow or fast?
no energy consumed–>free process
Fast!!!!
In the process of gluconeogenesis, what 2 organs start the process? What 3 things do they use to do it?
Liver & Kidneys amino acids lactate glycerol the 3 things listed above are all non-carbohydrate substrates
Is the liver or the kidneys a greater source of glucose for the blood?
The liver–by far!! 90% of the source!!
What is the only source of glucose for the blood after prolonged fasting?
the liver!! thru gluconeogenesis
What are 2 cycles that depend on the liver’s gluconeogenesis & then the delivery of that glucose to other tissues?
Cori Cycle (glucose-lactate cycle) Alanine Cycle (glucose-alanine cycle)
In gluconeogenesis, most of the enzymes are the same as glycolysis (just in reverse) except for which steps? Why?
the 3 irreversible energy waterfall steps.
These require different enzymes
Steps 1, 3, 10
Which enzymes replace steps 1, 3, & 10 in gluconeogenesis?
Step 1: glucose 6 phosphatase
Step 3: fructose 16 bisphosphatase
Step 10: Part 1: Pyruvate–>OAA (pyruvate carboxylase)
Part 2: OAA–>PEP (PEP carboxykinase)
What is the function of glucose 6 phosphatase? What process is it involved in?
Where is this enzyme found?
G6P–>Glucose
Gluconeogenesis
Endoplasmic Reticulum
What is the function of fructose 16 bisphosphatase? What process is this involved in? Where is this enzyme found?
Fructose 16 BP–>Fructose 6P
Gluconeogenesis
Cytoplasm
What is the function of PEP carboxykinase?
What process is this involved in? Where is this enzyme found?
OAA–>PEP
gluconeogenesis
Cytoplasm or mitochondria
What is the function of pyruvate carboxylase?
What process is this involved in? Where is this enzyme found?
Pyruvate–>OAA
gluconeogenesis
mitochondria
Which enzyme involved in gluconeogenesis is biotin dependent?
pyruvate carboxylase
Explain the bypass process in gluconeogenesis.
Need to convert pyruvate–>PEP.
Transport pyruvate across the mitochondrial membrane.
Convert to OAA thru pyruvate carboxylase (ATP dependent)
Either:
Stay in the mitochondrion.
Or leave the mitochondrion via malate or aspartate.
Convert OAA to PEP via PEP carboxykinase (GTP dependent)
What is the net cost of the bypass of gluconeogenesis?
1 ATP & 1 GTP per pyruvate
What is the driving force for the bypass in gluconeogenesis?
The fact that there is so much ATP & GTP & Pyruvate in the cell.
So…if the glucose 6 phosphatase enzyme is found on the luminal membrane of the ER….how does that help with gluconeogenesis???!!!
Well…there is a G6P transporter into the ER.
The G6Pase is on the luminal surface of the ER. It converts the G6P into Glucose & Pi.
There is a transporter to get the glucose & Pi out of the ER.
What is von Gierke’s Disease?
it is a disease caused by a defect in either the G6P transporter into the ER or the G6Pase. Sad.
What are 2 efficient feed-ins for gluconeogenesis b/c they are readily converted to pyruvate? What converts them?
Lactate (lactate dehydrogenase)
Alanine (a transaminase)
What is totally awesome about the conversion of lactate to pyruvate?
You don’t get any loss of NADH, b/c it generates NADH thru this conversion.
What do the cori & alanine cycles have in common?
They both convert into pyruvate & are then shuttled into the mitochondria to become OAA. Then they are shuttled back out to become glucose.
How many times must the Cori or alanine cycle be run in order to generate a glucose molecules?
TWICE!!!
How does the cost of gluconeogenesis differ b/w alanine & lactate as starting molecules?
Lactate–>Pyruvate generates NADH (2 total)
Alanine–>Pyruvate is free
Overall: takes less energy to make glucose from lactate.
Considering that you have to use 2 lactate or alanine molecules to make 1 glucose molecule…what are the energy costs at each step in the process?
Lactate: +2 NADH
Pyruvate carboxylase: -2 ATP
PEP carboxykinase: -2GTP
Phosphoglycerate Kinase: -2ATP
What does the body use for energy after a carb-heavy meal? After fasting?
Carb-heavy meal: glycolysis–lots of it!!
Fasting: fatty acid oxidation
T/F It is okay for gluconeogenesis & glycolysis to be running at the same time.
FALSE! It would be futile & just consume a lot of ATP. That is why it is so important to have regulators!!
What regulates pyruvate kinase? (allosteric)
An inhibitor is ATP. Another inhibitor is alanine.
Like, dude….stop the glycolysis already we have enough ATP. Just store & calm yourself down.
What regulates pyruvate carboxylase? (allosteric)
Acetyl CoA activates Pyruvate Carboxylase. ADP inhibits it.
Like, we have way too much acetyl CoA lying around…can be please go back home & be glucose. It’s crowded.
What regulates fructose 1,6 bisphosphatase? (allosteric)
Two activators are Citrate & ATP.
What regulates PFK1? (allosteric)
Citrate & ATP are both inhibitors.
What regulates F26BPase?
It is hormonally regulated.
How is fructose-2,6-bisphosphate involved in regulation?
It activates PFK1, meaning that it activates glycolysis.
It inhibits F-1,6BPase, meaning that it inhibits gluconeogenesis.
What is F26BP made from?
F6P!!!
What are the activators of pyruvate kinase? What type of activators are they?
Activator: Fructose-1,6-bisphosphate
allosteric
feed forward mechanism
What are the inhibitors of pyruvate kinase? What types of inhibitors are they?
Inhibitors:
ATP: allosteric
Alanine: allosteric
Glucagon Signaling
What are the activators of pyruvate carboxylase? What types of activators are they?
Activator:
Acetyl CoA: allosteric
What are the inhibitors of pyruvate carboxylase? What types of inhibitors are they?
Inhibitor:
ADP: competitive
What are the activators of PFK1? What types of activators are they?
Activator:
Fructose-2,6-bisphosphate: allosteric
What are the inhibitors of PFK1? What types of inhibitors are they?
Inhibitor:
ATP: allosteric
Citrate: allosteric
What are the inhibitors of Fructose-1,6-Bisphosphatase? What types of inhibitors are they?
Inhibitor:
Fructose-2,6-bisphosphate
competitive
What are the activators for fructose-1,6-bisphosphatase? What types of activators are they?
Activator:
ATP: allosteric
Citrate: allosteric
What is the overall way that gluconeogenesis is stimulated?
By the repression of glycolysis…at its waterfall sites or by the repression of the synthesis of the enzymes for the waterfall sites.
When does glucagon rise? What does it do?
Rises in response to low blood glucose during fasting.
Reduces glucose consumption.
Increase glucose production by the liver.
When does insulin rise? What does it do?
Rises in response to elevated blood glucose after a meal.
It stimulates glucose consumption in many tissues.
What 2 things generally increase the levels of glycolytic enzymes in the body?
Insulin
Glucose
What are the component parts of TPP?
thiamine= pyrimidine ring + thiazolium ring
pyrophosphate
What 2 things generally decrease the levels of glycoloytic enzymes in the body?
Glucagon Fatty Acids (present during starvation)
Aside from glucagon & fatty acids what else is used to increase blood glucose?
Epinephrine!
What is glucagon released from? In response to what? What does it do & how?
pancreatic alpha cells
Hypoglycemia
Raises blood glucose thru increase cAMP levels
What is the effect of epinephrine or glucagon in the liver? How?
It favors gluconeogenesis over glycolysis in the liver thru a rise in cAMP levels.
Does glucagon increase or decrease F26BP? What does this mean in terms of enzymes?
Decreases F26BP.
Means less activation of PFK1 & less inhibition of F16Bisphosphatase.
Decreases glycolysis in the liver.
Does insulin increase or decrease F26BP? What does this mean in terms of enzymes?
Increases F26BP.
Means more activation of PFK1 & more inhibition of F16Bisphosphatase.
Increases glycolysis in the liver.
F26BP activates/inhibits PFK1 in what way? Activates/inhibits F16Bisphosphatase in what way?
F26BP activates PFK1 allosterically
F26BP inhibits F16Bisphosphatase competitively.
What is the name of the special enzyme that has both kinase & phosphatase powers & forms Fructose 26BP?
Phosphofructokinase 2-Fructose-2,6-Bisphosphatase
What part of the special enzyme with 2 powers turns F6P–>F26BP?
Phosphofructokinase 2 part
What part of the special enzyme w/ 2 powers turns F26BP–>F6P?
Fructose-2,6-Bisphosphatase
In the human…where is the only place that has glucagon receptors?
the liver!!!
F6P–>F26BP is promoted by which hormone? Which activity of PFK2-F26BPase is promoted? Does this mean that the enzyme is phosphorylated or dephoshporylated?
Insulin
Kinase activity favored
Dephosphorylated enzyme
F26BP–>F6P is promoted by which hormone? Which activity of PFK2-F26BPase is promoted? Does this mean that the enzyme is phosphorylated or dephosphorylated?
Glucagon
Phosphatase activity favored
Phosphorylated enzyme
When there is a ton of F6P lying around…what happens to the PFK2-F26BPase activity?
F6P activates the kinase activity & inhibits the phosphatase activity. Thus, if there is a ton of F6P chillin’ around the house–>you’re gonna start to see some F26BP b/c that kinase will be going crazy. It does this allosterically.
Explain the process by which glucagon @ the liver slows glycolysis & increases gluconeogenesis.
Glucagon goes to the liver.
G protein active
adenylyl cyclase active
cAMP increases
PKA active
PPP inhibitor activated
Phosphoprotein phosphatase inhibited
Phosphatase activity of PFK2-F26BPase promoted
More F6P accumulates
F26BP can’t stimulates PFK1–glycolysis slows
F26BP can’t inhibit F16BPase–gluconeogenesis increases
When glucagon is high what happens?
Gluconeogenesis goes up & glycolysis goes down.
When insulin is high what happens?
Glycolysis is high & glucoeneogenesis is low.
Explain the process by which insulin @ the liver increases glycolysis & slows gluconeogenesis.
Insulin @ the liver activates a cAMP degrading phosphodiesterase.
cAMP decreases.
PKA not active.
PPI not active.
Promotes kinase activity of PFK2-F26BPase.
More F26BP accumulates
F26BP activates PFK1=more glycolysis
F26BP inhibits F16BPase=less gluconeogenesis.
What do glucocorticoids do?
They stimulate gluconeogenesis by inducing the synthesis of gluconeogenic enzymes.
When are glucocorticoids usu released?
during times of high stress
T/F The effects of glucocorticoids are often short-lived.
False. They are long-lasting.
What are some feed-ins (aside from carbs) for gluconeogenesis?
Lactate & Alanine go directly to Pyruvate
Other AA go to TCA intermediates to OAA & feed in
Glycerol (from triglycerides in fat) feeds in as DHAP
Odd chain fatty acids
T/F Even chain fatty acids are another good feed-in to gluconeogenesis.
FALSE!! Odd chain–yes.
Even chain–>acetyl CoA which can’t go backwards!
What are some feed-ins (aside from carbs) for gluconeogenesis?
Lactate & Alanine go directly to Pyruvate
Other AA go to TCA intermediates to OAA & feed in
Glycerol (from triglycerides in fat) feeds in as DHAP
Odd chain fatty acids
T/F Even chain fatty acids are another good feed-in to gluconeogenesis.
FALSE!! Odd chain–yes.
Even chain–>acetyl CoA which can’t go backwards!
What is the process for the breakdown of ethanol?
Ethanol
Acetaldehyde
Acetate
Acetyl CoA
What is the enzyme that catalyzes the reaction of ethanol to acetaldehyde & what does it give off?
Alcohol Dehydrogenase
Gives off NADH (can increase ATP eventually)
What is the enzyme that catalyzes the reaction of acetaldehyde to acetate? What does it give off?
Aldehyde Dehydrogenase
Gives off NADH (can increase ATP eventually)
What is the enzyme that catalyzes the reaction of acetate to acetyl CoA? What does it give off?
Acetyl CoA Synthase aka Acetate Thiokinase
AMP & PPi
Where does the reaction of acetate to acetyl CoA usu happen?
In the liver
the acetate travels thru the blood to the liver.
What is the rate limiting step of ethanol degradation?
the first step
ethanol to acetaldehyde
What does it take to saturate the first step of ethanol metabolism & what type of kinetics does it demonstrate?
1 drink saturates it
zero order kinetics
What is the Vmax of alcohol dehydrogenase & what does this mean in terms of blood alcohol levels?
Vmax=10 gram/hour
blood alcohol level increases 0.15g/hour
Antabuse (used to treat alcoholism) acts on which enzyme? What is another name for this drug?
aka disulfiram
acts on aldehyde dehdyrogenase
What causes “oriental flush”?
an isoform of aldehyde dehydrogenase…an isoform that has a lower affinity.
How many drinks can cause a toxic buildup of acetaldehyde? What does this do? What step is this?
1 or 2 drinks
cirrhosis
acetaldehyde–>acetate
What are the main products of ethanol metabolism? Given these products–>which pathways are inhibited?
Acetyl CoA
NADH
ATP
Glycolysis, TCA, & Beta oxidation are all inhibited.
With the buildup of NADH…what happens to lactate?
Buildup of NADH prevents the transformation of lactate–>pyruvate; & so the lactate builds up & is released into the blood as lactic acid
What 2 things can alcohol become?
Fatty Acids or Ketones
T/F Alcohol is both ketogenic & glucogenic.
FALSE. It is only ketogenic. NOT glucogenic.
So…you have a bunch to drink. How could this lead to ketoacidosis?
Tons of Alcohol
metabolized to a bunch of acetate.
Goes to the liver.
Becomes acetyl CoA
Becomes ketones–that can’t be metabolized
Therefore, the plasma pH will drop & you get ketoacidosis…
How do people who drink a lot get fatty liver? What is another name for this condition?
Hepatic Steatosis
they get this b/c the only option for acetyl CoA is ketone & fatty acid synthesis.
**you also get the release of a bunch of VLDL (bad cholesterol)
T/F The heart and kidneys have a bunch of acetylCoA synthase in their ER.
FALSE
the heart & SKELETAL MUSCLE
have a bunch of acetyl CoA synthase in their mitochondria…
T/F the liver metabolizes ketones.
FALSE
b/c the liver does not…only the extra-hepatic tissues do.
The extra hepatic tissues have the SCOT enzyme
Which enzyme is necessary to metabolize ketones into acetyl CoA? What is this reaction? Where is this enzyme found?
SCOT: acetoacetate-succinyl CoA transferase
Rxn:
Acetoacetate + Succinyl CoA–>Acetoacetyl CoA + Succinate
Found in extra-hepatic tissues (NOT the liver)
Which 2 vitamins does ethanol disrupt?
Vitamin A aka retinol
Vitamin B1 aka thiamine
How does ethanol disrupt Vitamin A? What is another name for this vitamin?
It is a competitive inhibitor of retinol dehydrogenase
**retinol
How does ethanol disrupt thiamine? What is another name for this vitamin? What disease can this cause?
Decreases absorption of thiamine
aka Vitamin B1
Wernicke-Korsakoff Syndrome
What does Wernicke-Korsakoff Syndrome do generally? What are 2 specific ways?
brain damage
- *Wernicke: encephalopathy–damages the hypothalamus & the thalamus
- *Korsakoff: psychosis–damages the area of the brain responsible for memory
T/F Ethanol is an energy source.
True. At the rate of 7.1kcal/g
Where does the ethanol metabolism begin in males? Where is it accomplished predominately?
begins in the stomach wall
predominately occurs in the liver
T/F the ethanol consumed doesn’t distribute to the different compartment of the body very well–>it mainly stays in the abdomen.
False. It distributes about equally.
How much alcohol consumption per day would be required to provide the energy of half the basal metabolic rate?
1-200 grams/day
What are the 3 stages of liver damage? And what happens at each stage? Caused by alcoholism.
Fatty Liver: b/c of increased triacylglycerol synthesis
Alcoholic Hepatitis: liver inflammation
Cirrhosis: hepatocytes die & there is replacement fibrosis
Ethanol in excess causes NADH in excess and leads to excessive amounts of which of the following & low amounts of which of the following? Lactate Pyruvate Malate OAA
Lots of Lactate & Malate
Not very much Pyruvate or OAA
What are some important pathways that are inhibited b/c of excess alcohol?
TCA
Fatty Acid Oxidation
Gluconeogenesis
How can lots of alcohol lead to hypoglycemia? What would be the results of this?
If there is already low liver glycogen, then hypoglycemia could result b/c gluconeogenesis is impossible.
Hypoglycemia will cause an increase in G3P & FFA
This will cause an increase in TAG & VLDL
How much energy does it take to go from pyruvate to glucose in gluconeogenesis?
4 ATP
2 GTP
2 NADH
How much energy does it produce to go from glucose to pyruvate in glycolysis?
2 ATP
2 NADH
