Week 15- Unit 4 Flashcards by Sean Rivera

_____ ______ is the primary distribution site for AA.

Skeletal Muscle

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Skeletal muscle can metabolize BCAA and release ______ and _____ to the brain and _______ to the gut.

Valine
Isoleucine

Glutamine

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Skeletal muscle will release _____, _____ and ______ that enter the blood to go to cells of immune system and end up in the liver.

AA
Alpha-Keto Acids
Alanine

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In the brain the _______ are required for Neurotransmitter synthesis. The brain will then release ________ to carry the Nitrogen to the _______.

BCAAs

Glutamine (can also come from Skeletal muscle to kindey)

Kidney

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The kidney and the Gut can release _____ that can be taken up by the liver to synthesize ______.

Alanine

Glucose

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In the Kidney, Glutamine (Arterial from brain and muscles), facilitates two primary reactions. It is Deaminated by _______ which provides a N that can absorb free H and act as a _____ system in urine. This will allow for a reabsorption of ______ to a greater extent.

Glutaminase (turns it into glutamate)

Buffering

Bicarbonate (renal vein)

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The Glutamate in the kidneys can be completely Oxidized in the _______ cycle after it is deaminated by _______ to _______.

TCA

Glutamate Dehydrogenase

Alpha-KetoGlutarate

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The free A-KetoG in the kidney can be used to synthesize what 4 things?

The primary reason for this is to provide necessary compounds for the kindey itself. If it makes Glucose, then it will use it itself.

Glucose
Pyruvate
Serine
Glycine

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In some cases the kidney can be a site of _______ in cases such as starvation. But the body is not reliant on this process in the Kidney.

GNG

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In the kidney the pathway of Glutamine can go as follows:
Glutamine ——> Glutamate——>Alpha-KG—–> TCA cycle into _______. This can leave the MT and in the cytosol will convert to ______. This can then be used for GNG or to synthesize _______ which can be transaminated to Serine.

OAA

PEP (using PEPCK enzyme)

Alanine

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if Alanine is transaminated to Serine, what does the leftover Alanine turn into?

Pyruvate

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In the kidney, _____ provides substrate for energy as well as Ammonia for buffering.

Glutamine

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In the Renal Tubule cell, Ammonia can absorb a _____ to become Ammonium Ion (NH4). Ammonium ______ be taken back up/ diffuse back through plasma membrane as it is a ______molecule so it is excreted in urine. This is one way to regulate system buffering through excretion of NH4 (charged protons join NH3)

Hydrogen Ion

Cannot

Charged

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In the skeletal muscle the catabolism of ______ . Branched chain amino-trasferases are highly expressed in all places except the ______.

BCAAs

Liver

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Branched Chain Amino-Transferases will use a-KG with BCAAs to transform them into _____________ and ________.

Branched chain - Alpha Keto Acids

Glutamate (has NH3+)

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Glutamate will facilitate the _____ nucleotide cycle. The _______ _______ enzyme will convert Glutamate into Glutamine. But this will only happen after another Gluamate has been transaminated to create aspartate from OAA then leading to Purine Nucleotide cycle, or from action of _____ on the Glutamate.

Purine

Glutamine synthetase

GLutamate Dehydrogenase (GDH)

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What two BCAAs can enter the TCA cycle as Acetyl CoA?

Isoleucine (can be Succinyl CoA too)

Leucine

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What two BCAAs can enter the TCA cycle as Succinyl CoA?

Isoleucine

Valine

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If the BCAA has entered the TCA cycle as Succinyl CoA (valine or isoleucine), then it can either go backwards and be turned into ______ then ______ then _______. Or it can move forwards in the cycle and as _____ be converted to ______ which is transaminated to ______.

A-KG then Glutamate then Glutamine

Malate —->pyruvate—->Alanine

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What are two non-toxic carriers of Ammonia in the body that can be generated through the TCA cycle?

Alanine (from maltate to pyruvate)

Gluamine (from A-KG to Glutamate )

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What is the enzyme that is reversible and can change Pyruvate to Alanine and Alanine to Pyruvate ?

Alanine Aminotransferase

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The catabolism of AA in the intestinal epithelial cells is the ________ from the postprandial state (diet) and the postaborptive state from the blood.

Same

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In the postabsorptive state (blood) most of the AA enter as what 3 things into the intestinal epithelial cells?
What 2 main things will the go back into the blood as after the AA are oxidized?

Glutamine, BCAAs, Ketone bodies

Alanine or Lactate

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The ______ cells and the _____ in the brain both synthesize _____ as it is required as a precursor for many neurotransmitters.

Astroglial
Neurons

Glutamine

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The substrates for Glutamine synthesis in the brain primarily come from _______ and _____ in the blood that cross the blood brain barrier.

BCAAs | NH3 crosses and is made into NH4 once in brain

Once the BCAAs are in the brain, they are ________ by __________ to generate Glutamate. This is then acted upon by what enzyme to make Glutamine?

deaminated branch-chain aminotransferases -Glutamine synthetase (adds NH4 to Glutamate)

In nitrogen balance, anabolism (synthesis) and catabolism (degradation) of proteins are about equal in balance and have a turn over of about ____ to ____ grams of protein per day.

300g to 600g

In nitrogen balance, if synthesis exceeds degradation, then you are in a _______ balance- occurs during growth, pregnancy, and repair.

Positive

In nitrogen balance if degradation is greater than synthesis then you are in a _______ balance - occurs in cases of severe injury (burns), starvation, wasting diseases (sepsis). Otherwise nitrogen balance is neutral.

Negative

In a disease state, during the initial immune response with elevated body temperature, nitrogen balance will become _________ and over the course of disease progression the cumulative nitrogen balance will be______.

negative negative

Bacterial products will activate the immune cascade starting at the _________. This will secrete any number of cytokines and chemokines. ____ , ______, and _______ are poly-peptides requiring AA and will be sent to liver.

Macrophage TNF IL-1 IL-6

With activation of Macrophages, they will secrete _____and ______ to the adrenal cortex that will trigger the production/secretion of _______.

TNF IL-1 Glucocorticoids

The Glucocorticoids released from the _____ _____ during an immune response will travel to the muscles and trigger ______ _______. This will also decrease AA uptake and AA synthesis.

Adrenal cortex Protein catabolism (AA are then shuttled to liver for GNG)

In the liver during an immune response, the AA uptake will _____, protein synthesis will ______ and acute phase protein synthesis will _______. This will contribute to the negative nitrogen balance during a disease state.

increase increase increase

What 2 things will hit the Skeletal muscle to trigger a decrease in AA uptake, decrease in AA synthesis and increase in Protein catabolism for transport to the liver ?

Epinephrine (From Adrenal medulla triggered by brain) | Glucocorticoids (Adrenal cortex signaled by macrophages)

A 4 year old child after a meal will display what metabolic pattern in regards to : Nitrogen balance? GNG? Fatty Acid Oxidation?

nitrogen balance- positive GNG- decreased FA oxidation- decreased

The four primary hormones are ?

Insulin Glucagon Epinephrine Cortisol

Insulin (promotes growth) will stimulate AA _____ and Protein ______.

uptake synthesis

Insulin signals through a receptor ______ _______. When bound by Insulin, the receptor will ________ and recruit _______.

Tyrosine kinase Autophosphorylate IRS

Once IRS is recruited it is _________ and this will recruit __________ by binding the phosphotyrosine residues via the _______ domain.

Phosphorylated Grb2 SH2 domain

Once IRS is recruited, besides Grb2, it will phosphorylate and recruit _______ and ________. Both of these are attached in the membrane and interact with PIP3.

Phospholipase C Protein Kinase (PI3-K)

In insulin sensitive cells, the binding of insulin will trigger translocation of ______ _______ to the plasma membrane. This activity is present mostly on ________ and _______.

Glucose transporters (GLUT 4 primarily) Skeletal Muscle and Adipose

________ glucose transporter is insulin insensitive and is on ________. This is important because they lack MT and are dependent on Glucose for energy.

GLUT 1 RBC (and Brain)

_______ glucose transporter is insulin insensitive and is primarily found on the Liver (or kidney, pancreatic B-cells, intestinal cells) and is a high capacity, low affinity transporter. It may be used as the glucose sensor in the pancreas.

GLUT 2

______ glucose transporter is the main one for the neurons in the brain. It is a High affinity system and the main transporter in the CNS.

GLUT 3 (however GLUT 1 is the primary for the Brain not 3)

________ is the insulin SENSITIVE transporter found in adipose, skeletal muscle , and heart muscle. High affinity system.

GLUT 4

_______ is actually a fructose transporter and is found on the intestinal epithelium and Spermatozoa.

GLUT 5

What are the three main regulatory steps in Glycolysis ?

1. Glucokinase/Hexokinase (phosphorylates Glucose in the cell) 2. conversion of G-6P to Fructose 6-P by Phosphofructokinase 1 3. conversion of PEP to Pyruvate by Pyruvate kinase

What can inhibit Phosphofructokinase 1 in Glycolysis?

ATP | Citrate

What can inhibit Pyruvate Kinase in Glycolysis?

Phosphorylation (cAMP-dependent) Alanine

In the fed state, Insulin will activate ______ _____ that will dephosphorylate ______ ______ and initiate Glycogen production from UDP-Glucose. This can occur in the liver and skeletal muscle.

Protein Phosphatase Glycogen Synthase

In FA synthesis, _______ from Glucose 6-P entering the Pentose pathway will be required as will _____ in the cytosol be required that comes from TCA cycle intermediate that is shuttled out of the MT when elevated.

NADPH Citrate

Citrate in FA synthesis is used as a substrate to eventually synthesize _________. Citrate is first acted on by _____ ______ to change it back to OAA and ________.

Malonyl CoA Citrate Lyase Acetyl CoA

Malonyl CoA will be the required substrate in FA synthesis to generate _______.

Palmitate

Citrate will stimulate _____ _________ which is the regulatory enzyme for FA synthesis and is responsible for converting Acetyl CoA to _______.

Acetyl CoA Carboxylase Malonyl CoA

In the Fed state involving FA synthesis, Insulin will stimulate a ________ that dephosphorylates the AcetylCoA Carboxylase converting it to the ______ form.

Phsophatase Active (starts FA synthesis)

How does the Acetyl CoA Carboxylase get inhibited or turned off from continuing FA synthesis?

1. Low energy levels activates AMP-activated protein kinase to phosphorylate the enzyme and inactive it 2. High levels of its own downstream product Palmitoyl CoA can inhibit it

In the Fed state , the primary fuel usage in most tissues is ________ .

Glucose Liver- GLUT 2 Muscle and Adipose- GLUT 4 Brain- GLUT 1

The Urea cycle is ______ in the fed state and _____ in the fasting state. In the fasting state there is ______ deamination of AA for GNG and _____ Urea synthesis.

stable increased increased increased

In the fasted state the Fructose 2,6 bisphosphatase enzyme is _______ by Protein kinase A and is acting as a phosphatase. If it was not phosphorylated it would be acting as ___________ (same overall enzyme unit). This will either increase Fructose 2,6 bis-P levels or decrease them. in GNG, you need decreased F-2,6 bisP levels to decrease inhibition of _________ to allow the pathway to go backwards.

Phosphorylated Phosphofructokinase 2 Fructose 1,6 bisphosphatase

In the fasted state, cAMP (from high glucagon) in the adipose will activate ______ _____ ______ by phosphorylating it and this will break down ____ into 3 FA and 1 Glycerol for export.

Hormone-sensitive Lipase Triacylglycerol (TG)- through hydrolysis

After Hormone sensitive lipase in the Adipose has broken down the TG and exported it , the ____ can be used as energy by converting it to _____ in skeletal muscle/ liver, and the Glycerol will be used in ______.

``` FA Acetyl CoA (for beta oxidation- cant be used for GNG) ``` GNG

In the fasting state, Glucocorticoids like Cortisol (besides glucagon) will also help stimulate Lipolysis in the adipose , and will be most important to stimulate protein degradation in muscle to supply AA primarily as ______ and _______ for usage as the primary carbons to synthesis Glucose in ______.

Alanine Glutamine GNG

In the fasted state , FA can be beta oxidized in the liver and Muscles to make _______. This substrate can be used to make _____ in the liver (for blood circulation to muscles back to AcetylCoA) or go directly into the ____ cycle for oxidation for energy if in the muscles.

Acetyl CoA Ketone bodies TCA

Fuel usage in the fasted state - the brain and the RBC will mainly use ______ with the GLUT 1 transporter, while the adipose, skeletal muscle, and liver are using ______. Although the skeletal muscle can use any _____ for energy as well. Under these conditions adipose and muscle are not using any glucose because their transporters ______ are off as they are insulin sensitive as glucose is low.

Glucose Fatty Acids Ketones GLUT 4

In the fed state, insulin will stimulate a ______ which will initiate dephosphorylation that activates many enzymes.

phosphatase

``` Insulin will lead to the dephosphoryation of : _____-2 (kinase activity now active) Pyruvate ______ (now active) Glycogen ______ (now active Phosphorylase _____ (now active) Glycogen ________ (now inactive) Pyruvate _______ (now active) Acetyl-CoA _______ (now active) ```

``` PFK-2 Pyruvate kinase Glycogen synthase Phosphorylase kinase Glycogen phosphorylase Pyruvate dehydrogenase AcetylCoA carboxylase (FA synthesis) ```

Insulin dephosphorylation of many enzymes leading to their activation will lead to what 3 active processes?

Glycolysis FA synthesis Glycogen synthesis

``` Glucagon release will lead to phosphorylation of the following enzymes: PFK-2 (_______ activity now active) Pyruvate kinase (now _____) Glycogen synthase (now _____) Phosphorylase kinase (now ____ ) Glycogen phosphorylase ( now ___) Pyruvate _________ (now ______) Acetyl CoA carboxylase (now ______) ```

``` phosphatase inactive inactive active active dehydrogenase- inactive inactive ```

In the Starvation state, Glycogenolysis is _______ GNG is ______ and just enough for RBC Lipolysis is ________ for fuel for beta oxidation. Muscle catabolism is ______ to conserve. Urea synthesis is ____ because of less muscle breakdown so fewer AA to degrade. Ketone body synthesis has ________ to include brain usage.

depleted (absent) very low (just enough for RBC) increased lipolysis decreased - conserve muscles decreased Urea increased Ketones

In the Diabetic Ketoacidosis patient, Di Abietes, she is a type 1 Diabetic (15 years), and is found unconcious after being sick for 24 hours with : Serum Glucose:400mg/dL pH is 7.15 What is the ratio of insulin/glucagon? What pathways are activated in this ratio?

Insulin is <1 to Glucagon (low insulin, high glucagon) ``` Glycogenolysis Beta-oxidation (ketones will be present too) GNG Lipolysis Urea cycle ```

in the Diabetic ketoacidosis patient, Di Abietes, Ketones are found in the blood due to elevated ________ levels from the constant release of FA from the adipose that is beta-oxidized in the liver (insulin not present to stop the release). The ketone bodies will ______ the blood pH.

Acetyl-CoA Acidify

In the Diabetic Ketoacidosis patient, why is the Glucose elevated?

1. GNG very active (urea is elevated)- AA catabolism active with hormone signaling (no insulin to stop it) 2. Lack of insulin reduces glucose uptake into muscle and adipose (GLUT 4 is insulin sensitive)

True or False: Administering insulin to the Diabetic Ketoacidosis patient will help reduce blood glucose by = Increase in GLUT 4 translocation to the plasma membrane.

True - this will increase glucose transport into cell

True or False: Administering insulin to the Diabetic Ketoacidosis patient will help reduce blood glucose by = Dephosphorylation on glycogen synthase.

True- it will turn on glycogen synthesis and help reduce blood glucose levels

True or False: Administering insulin to the Diabetic Ketoacidosis patient will help reduce blood glucose by = Increased activity of Pyruvate Kinase.

True- (phosphatase will dephosphorylate pyruvate kinase to activate it) -increases flux through glycolysis

True or False: Administering insulin to the Diabetic Ketoacidosis patient will help reduce blood glucose by = Phosphorylation of acetyl CoA carboxylase.

False - does not occur in presence of insulin, insulin presence will dephosphorylate AcetylCoA Carboxylase to active it in FA synthesis

The ketones Acetoacetic acid and Beta-Hydroxybutyric acid are both considered _____ acids as are most biological acids.

Weak

Acetoacetate has a pKa of _______. B-Hydroxybutyrate has a pKa of _____. This means both with be in the ______ form in the body (released their H+) and have a negative charge. Therefore increasing the presence of H+ in the blood and _____ the blood pH (acidifying).

3. 62 4. 41 Anion decreasing

In order to combat and try to level out the acidification of the blood pH caused by the elevated Ketones, the body will us _____ as a regulatory buffer. This is evident in the respiration changes in the Diabetic Ketoacidosis patient.

Bicarbonate ( HCO3+ H+)

Bicarbonate is made by the enzyme _____ ______ combining ____ and _____ to make _____ ____.

Carbonic anhydrase CO2 and H20 Carbonic acid (then a Hydrogen can dissociate to become Bicarbonate - direction of reaction depending on CO2 levels)

The direction of the reaction of _______ acid levels vs. _______ as a buffer system depends on the levels of ______ in the body.

Carbonic acid Bicarbonate CO2

As CO2 levels in the body increase, this will help _______ pH. (respiratory compensation)

decrease (more bicarbonate)

As CO2 levels decrease in the body, this will help buffer to _____ pH. (respiratory compensation)

increase (more carbonic acid)

pH of blood is normally around _______.

pH 7.4

In the Metabolic Ketoacidosis patient Blood pH was 7.15 Is she in Metabolic Acidosis or Alkalosis?

Metabolic Acidosis

Di Abiete's arterial blood was 23mmHg (ref 37 to 43) and her serum bicarbonate was 8mEq/L (ref 24 to 28).. What direction did the bicarbonate buffer shift to compensate for this change (left or right)?

Left shift -she has increased respiration to decrease levels of CO2 which will then help increase Carbonic acid to fight the increase in H+ (blood pH is acidic) - so level of bicarbonate was very low (carbonic acid is high instead)

Why is Di Abiete Metabolic Acidosis patient presenting with elevated BUN (blood urea nitrogen)?

GNG is very active and so a lot of Ammonia is being produced

Patient Linda - 18 month old female- found unresponsive , Blood glucose was 20mg/dL (very low). Urinalysis revealed elevated levels of Glutaric, ethylmalonic, dicarboxylic acids. She has not eaten the night before nor recently. Before treatment , what is the ratio of insulin to glucagon? What pathways are activated?

insulin <1 compared to glucagon (fasted state) ``` Glycogenolysis Beta-oxidation GNG Lipolysis Urea Cycle ```

In patient Linda, presenting with hypoglycemia yet she is in a fasted state, what is the enzyme she is missing related to Beta-Oxidation and what length chain FA can she not process?

Missing Acyl-CoA Dehydrogenase specific to Medium chain FA

What are the 3 effects of Linda not having the first enzyme in Beta oxidation for medium chain FA (missing Acyl-CoA dehydrogenase) ?

Decrease in FAD and NAD reduction Decrease in Acetyl-CoA production Increase in Medium chain FA in the Mitochondria

The majority of FA (Fatty Acyl CoA) released in lipolysis are _____ chain, as the synthesis of Palmitate or _______ FA are denovo in the body. These require _______ to be transported across the MT membrane.

long C16 Carnitine

Medium chain FA are ____ to ___ carbons. Therefore Long chain FA in the MT will turn into Medium chain FA after _______ cycles through Beta oxidation. Then _______ will occur in the MT.

8 to 10 2 to 3 Accumulation

Medium chain FA are oxidized through ______ ______. This process will generate the _______ acids that are seen in hypoglycemic Linda's Urine. This explains one of her clinical symptoms.

Omega oxidation Dicarboxylic Acids

In hypoglycemic patient Linda, beta oxidation is impaired due to her lack of __________ _______ enzyme to process the Medium chain FAs. This means ______ are not generated due to lack of _____. FFA can then not be used for energy and increases reliance on _______.

Acyl-CoA Dehydrogenase (MCAD) Ketones Acetyl CoA Glucose (will make it very low in blood because the liver and adipose and muscle now can only use it)

The decrease in Acetyl CoA caused by the Acyl-CoA dehydrogenase problem (inhibiting Beta-oxidation of medium chain FA) will decrease _____ then reducing the energy needed for _____. This lowered Acetyl CoA will reduce the allosteric activating power of it upon _______ ______. All of this will inhibit GNG and decrease the livers ability to make Glucose.

ATP GNG Pyruvate Carboxylase (converts Pyruvate to OAA with Biotin cofactor)