Choudhury CIS

Question 1

Amino Acids in Metabolism- Fed State

Answer 1

Amino acids brought in by digestion
Travel to liver 
- Nitrogen to synthesize proteins
--- Particularly albumin
--- Amino acids released into blood for other tissues

Carbon converted to glucose, ketone bodies or triacylglycerols
- Stored or travel to other tissues

Question 2

Amino Acids in Metabolism- fasting state

Answer 2

Amino acids released from protein breakdown

• Some released into blood directly
• Some lose the nitrogen to glutamine or alanine to be shuttled through the blood
• – In the kidney, glutamine delivers ammonia into urine
• – In the liver, alanine and other aa deliver nitrogen for urea
• ——-Carbons are converted into glucose, etc.

Question 3

Clay-colored stools mean

Answer 3

no bilirubin in the feces

Question 4

tea colored urine

Answer 4

lacking bilirubin for coloration

Question 5

clay-colored stools and tea colored urine indicate

Answer 5

blockage - tumor, stones, parasites- of hepatobiliary tract

Question 6

types of hepatitis related to food

Answer 6

A or E

Question 7

what should pts with liver issues avoid?

Answer 7

alcohol, NSAIDs, things that can increase hepatotoxicity

Question 8

Hyper-ammonemia

Answer 8

In adults, caused by liver failure
Toxic effects of ammonia
- Brain swelling due to osmotic imbalance (High ammonia and glutamate in astrocytes)
- Astrocytes produce glutamine (From a-ketoglutarate and ammonia–> Exacerbates osmotic imbalance–> At high enough concentrations, opens mitochondrial permeability transition pore)

Decreases glutamate concentration
- An excitatory neurotransmitter

Question 9

Glutamate

Answer 9

Central to urea production
Provides the two nitrogens Glutamate
- One in ammonium ion
—– From transamination of other amino acids followed by glutamate dehydrogenase reaction
- One in aspartate
—— Glutamate transaminates oxaloacetate (aspartate’s corresponding a-keto acid) to aspartate

Question 10

Transamination: Removing the nitrogen

Answer 10

Nitrogen transferred to a-ketoglutarate
- Produces glutamate

The amino acid becomes its corresponding a-keto acid

Question 11

Transamination: Production of Ammonia

Answer 11

Glutamate is deaminated by glutamate dehydrogenase:
a-ketoglutarate
Ammonium ion (NH4+)
reversible

Other sources of ammonia:
Deamination of other amino acids
Purine nucleotide cycle in brain and muscle
Bacteria in the gut

Question 12

Glucose/Alanine Cycle

Answer 12

In muscle, glucose is metabolized via glycolysis
- Produces pyruvate
Pyruvate is transaminated by glutamate to
form alanine
Alanine is exported and used as one of two
main nitrogen carriers in the blood
Travels to the liver

Question 13

transamination reactions

Answer 13

move an amine group.

Question 14

Glutamine

Answer 14

The other main carrier (of nitrogen)

In somatic cells and liver

Glutamate can accept a second Nitrogen to
form glutamine

In liver:
- Reaction used to prevent any ammonia that escaped urea production from leaving liver

In somatic cells

• Glutamine released into circulation to go to liver
• Glutamine used to produce ammonia for urea cycle

Question 15

Urea Cycle

Answer 15

In Liver Urea Cycle

Nitrogen enters as ammonium ion or aspartate

In mitochondria

• Ammonium ion is used to form carbamoyl phosphate
• Reacts with ornithine to produce citrulline
• Transported to cytosol

In cytosol

• Aspartate reacts with citrulline
• Arginine is generated
• Arginine is cleaved to release urea and regenerate ornithine

Question 16

lactulose

Answer 16

a sugar, not well absorbed, inhibits bacterial transcription

can cause ostmotic diarrhea

Question 17

Urea Cycle Enzyme Defects

Answer 17

Accumulation of substrates or intermediates before the block
Changes extent of elevation of glutamine and ammonia

Low citrulline means defect before the step that produces citrulline, e.g.

Question 18

Carbamoyl phosphate syntetase deficiency

Answer 18

Urine orotate- low
blood citrulline- low
blood arginine- low
Blood NH3- High

Question 19

Ornithine transcarbamoylase defect

Answer 19

urine orotate- high
blood citrulline- low
blood arginine- low
blood NH3- high

Question 20

Argininosuccinate synthetase deficiency

Answer 20

blood citrulline- High (< 1000 microM),
blood arginine low,
blood NH3 high

Question 21

Argininosuccinate lyase deficiency

Answer 21

Blood citrulline- high (over 200 microM),
blood arginine low,
blood NH3 high

Question 22

ARginase defect

Answer 22

blood arginine high

blood NH3 moderately high

Question 23

Orotic Acid/Orotate

Answer 23

Carbamoyl phosphate Created in the mitochondria to allow ammonia to enter the urea cycle

Carbamoyl phosphate accumulation

• When Ornithine transcarbamoylase is deficient
• Excess carbamoyl phosphate enters the pathway for pyrimidine biosynthesis
• Creates the intermediate, orotate or orotic acid
• – Elevation in urine is indicative of urea cycle defect

Question 24

Degradation of Amino Acids

Answer 24

Glucogenic Carbons used to create glucose in the liver
- Produce intermediates of the TCA Cycle
- All non-essential amino acids can be used
to produce glucose

Ketogenic

• Carbons used to create ketone bodies or their precursors
• – Acetyl-CoA or acetoacetate
• Lysine and leucine are strictly ketogenic

Can be categorized as both
- Tryptophan, isoleucine, threonine, phenylalanine and tyrosine

Question 25

Homocystinuria

Answer 25

Autosomal Recessive Deficiency: Cystathione synthase ``` Presentation: Cardiovascular disease - Deep vein thrombosis - Thromboembolism - Stroke Dislocation of the lens Mental retardation Marfanoid habitus ``` ``` Accumulation of Substrates: No cysteine Elevated methionine Elevated homocysteine - Homocystine is the oxidized disulphide form ``` Can also arise from Vitamin Deficiency B12 and Folate: Homocysteine methyltransferase - Methylates homocysteine to methionine Serum methionine levels low

Question 26

Coenzymes

Answer 26

Vitamin B12 Folate Vitamin B6 (Pyridoxal Phosphate) - Key coenzyme for amino acid metabolism - Required for transamination reactions - -- Enzyme bound pyridoxal phosphate - -- Reacts with an amino acid - -- Acquires the amino group and releases a-ketoacid - -- Reacts with another a-ketoacid - -- Releases the amino group to produce an amino acid - -- Pyridoxal phosphate regenerated Administered to treat homocystinuria (Free PLP catalysis)

Question 27

A diagnosis of type I homocystinuria was made (Cystathione synthase deficiency) based on elevated methionine levels:

Answer 27

Increased conversion of homocysteine to methionine due to increased availability of homocysteine. In type II and III (deficiency in conversion of B12 and folate respectively) there is not increased methionine because these coenzymes are required for homocysteine methylation

Question 28

Treatment of homocystinuria

Answer 28

directed toward reduction of elevated homocysteine and methionine: A diet low in methionine Low-protein diet: vegetarian or vegan Vit B12, L-cystine and choline (methyl-donor) supplementation Very high doses of oral Vitamin B6 Free PLP catalysis of homocysteine to cysteine 50% of type I patients are Vit B6 “responders”

Question 29

Alcoholic Hypoglycemia

Answer 29

Metabolism of Alcohol - Ethanol rapidly converted to acetaldehyde in liver--> Then converted to acetate - Both reactions require NAD+ - -- [NADH]/[NAD+] increases in the liver NAD+ is required for gluconeogenesis - Major precursors (lactate, alanine and glycerol) cannot enter pathway because the increased [NADH]/[NAD+] drives the reactions backwards

Question 30

Patient presentation in alcoholic hypoglycemia

Answer 30

Tremulous, sweating, increased HR - Adrenergic nervous system stimulation - - Hormone release counter-regulatory to hypoglycemia - - Glucagon, growth hormone, cortisol and epinephrine Confused, combative, slurred speech, seizure - “Neuroglycopenic symptoms” -- Insufficient glucose to brain tissue - Wernicke encephalopathy (thiamine deficiency) -- Includes oculomotor dysfunction and gait ataxia

Question 31

Maintenance of Blood Glucose Levels

Answer 31

Maintained by liver Glycogenolysis - During fasting - Mostly depleted after more than 12 hours Gluconeogenesis - During starvation - Increases as glycogen reserves decrease - Only source after 24 hours of fasting

Question 32

Gluconeogenesis

Answer 32

Most steps are a reverse of glycolysis Major precursors: - Lactate - -- Oxidized to pyruvate by lactate dehydrogenase - Alanine - -- Converted to pyruvate by alanine aminotransferase - Glycerol-3-phosphate - -- Oxidized to DHAP by glycerol-3-phosphate dehydrogenase

Question 33

4 reactions required to circumvent irreversible steps in glycolysis

Answer 33

The conversion of PEP to pyruvate is irreversible Pyruvate carboxylase - Reduces OAA to malate so it can leave the mitochondria and be converted back into OAA ``` Phosphoenolpyruvate carboxykinae (PEPCK) - Converts OAA to PEP ``` NAD+ required to proceed - Conversion of OAA to Malate and back to OAA - Reduced due to alcohol metabolism Kinases are not reversible in function: 1. Fructose-1,6-bisphosphatase - - Hydrolyzes one phosphate to F-6-P 2. Glucose-6-phosphatase - Hydrolyzes one phosphate to glucose - Occurs in ER so free glucose is transported out of cell - Only expressed in liver so only source of blood glucose through gluconeogenesis

Question 34

treatment of alcoholic hypoglycemia

Answer 34

Vitamin B1 (thiamine)!!! Thiamine is converted to thiamine pyrophosphate (TPP) (requires magnesium) 3 important reactions in the body that require the following co-factors TPP; Lipoic acid; Coenzyme A; FAD(H2) “Riboflavin”; NAD (H) “Niacin” (Tender, Loving, Care, For, Nancy)

Question 35

So what are the 3 important reactions in the body that require the following co-factors ?? TPP; Lipoic acid; Coenzyme A; FAD(H2) “Riboflavin”; NAD (H) “Niacin” (Tender, Loving, Care, For, Nancy)

Answer 35

1. Pyruvate-->PDH --> Acetyl CoA 2. a keto glutarate --> a ketoglutarate dehydrogenase --> succinyl CoA 3. Leucine, Isoleucine, Valine --> branched chain ketoacid dehydrogenase --> Acetyl CoA, Propionyl CoA In absence of the cofactors, the enzymes in the reactions either do not work or Work very slowly. Reactions 1 and 2 are important for glycolysis, TCA cycle and ETC to produce ATP

Question 36

In the absence of these critical reactions...

Answer 36

reactions 1 and 2 are important for glycolysis, TCA cycle and ETC to produce ATP Without the enzymes functioning there will be NO ATP production With i/v glucose, there will be a massive production of pyruvate then to lactate As pyruvate cannot enter the TCA cycle Huge amount of lactate will cause lactate acidois and eventual death Glucose cannot enter hexose monophosphate shunt pathway and no production of NADPH, cell is not protected from stress due to increase reactive oxygen species, results in either cellular death or activation of apoptosis Patient at risk of Wernicke-Korsakoff Syndrome, cerebellar degeneration and cardiovascular dysfunction

Question 37

Thiamine deficiency results in:

Answer 37

decreased ATP production increased Lactic acid production will lead to acidosis increased a-keto acids increased NADH production will inhibit glycolysis decreased NAD+ will inhibit glycolysis decreased NADPH (via HMPS) production increased Cell stress increased Apoptosis/Cell death Patient at risk of Wernicke-Korsakoff Syndrome, cerebellar degeneration and cardiovascular dysfunction

Question 38

treatment of alcoholic hypoglycemia

Answer 38

give thiamine 100 mg i/v before administering glucose containing i/v fluids and then to continue this dose for several days. Severe hypoglycemia must be corrected within 6-10 hours to prevent permanent neurological damage. The physician must also correct: - Acidemia Beta-hydroxybutyrate and acetoacetate to increase bicarbonate - Ketoacidosis Dextrose administration will increase insulin and decrease glucagon Volume depletion From vomiting/diarrhea or decreased intake; saline or isotonic electrolyte balanced solution administration Deficiencies Potassium and sodium (vomiting, diarrhea, urinary loss), magnesium (pancreatitis and diarrhea), phosphate (movement out of cells) and thiamine and vitamins (malabsorption and malnutrition)