Choudhury CIS Flashcards
Amino Acids in Metabolism- Fed State
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
Amino Acids in Metabolism- fasting state
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.
Clay-colored stools mean
no bilirubin in the feces
tea colored urine
lacking bilirubin for coloration
clay-colored stools and tea colored urine indicate
blockage - tumor, stones, parasites- of hepatobiliary tract
types of hepatitis related to food
A or E
what should pts with liver issues avoid?
alcohol, NSAIDs, things that can increase hepatotoxicity
Hyper-ammonemia
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
Glutamate
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
Transamination: Removing the nitrogen
Nitrogen transferred to a-ketoglutarate
- Produces glutamate
The amino acid becomes its corresponding a-keto acid
Transamination: Production of Ammonia
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
Glucose/Alanine Cycle
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
transamination reactions
move an amine group.
Glutamine
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
Urea Cycle
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
lactulose
a sugar, not well absorbed, inhibits bacterial transcription
can cause ostmotic diarrhea
Urea Cycle Enzyme Defects
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.
Carbamoyl phosphate syntetase deficiency
Urine orotate- low
blood citrulline- low
blood arginine- low
Blood NH3- High
Ornithine transcarbamoylase defect
urine orotate- high
blood citrulline- low
blood arginine- low
blood NH3- high
Argininosuccinate synthetase deficiency
blood citrulline- High (< 1000 microM),
blood arginine low,
blood NH3 high
Argininosuccinate lyase deficiency
Blood citrulline- high (over 200 microM),
blood arginine low,
blood NH3 high
ARginase defect
blood arginine high
blood NH3 moderately high
Orotic Acid/Orotate
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
Degradation of Amino Acids
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
Homocystinuria
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
Coenzymes
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)
A diagnosis of type I homocystinuria was made (Cystathione synthase deficiency) based on elevated methionine levels:
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
Treatment of homocystinuria
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”
Alcoholic Hypoglycemia
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
Patient presentation in alcoholic hypoglycemia
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
Maintenance of Blood Glucose Levels
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
Gluconeogenesis
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
4 reactions required to circumvent irreversible steps in glycolysis
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:
- Fructose-1,6-bisphosphatase
- - Hydrolyzes one phosphate to F-6-P - 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
treatment of alcoholic hypoglycemia
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)
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)
- Pyruvate–>PDH –> Acetyl CoA
- a keto glutarate –> a ketoglutarate dehydrogenase –> succinyl CoA
- 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
In the absence of these critical reactions…
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
Thiamine deficiency results in:
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
treatment of alcoholic hypoglycemia
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)
