Ammino Acid Metabolism Lecture Sep 5 Flashcards
What are the three cofactors for enzymes in amino acid metabolism?
What are their purposes?
Pyridoxal Phosphate (PLP) is used for transaminations, deaminations, and some carobn chain transfers
Tetrahydrofolate (FH4) is used for one carbon transfers
Tetrahydrobiopterin (BH4) is used for aromatin ring hydroxylations
What nine amino acids are considered essential in the diet? Why do they need to come from the diet?
They have to come from the diet because the body cannot synthesize them.
Use the nmemonic: M.V. Pitthall
Methionine
Valine
Phenylalanine
Isoleucine
Tryptophan
Threonine
Histidine
Arginine (important for children, but not for adults)
Leucine
Lysine
What essential amino acid does tyrosin require for syntehsis?
phenylalanine.
So if phenylalanine is low, then tyrosine becomes an essential amino aicd in the diet because it cannot be synthesized
What essential amino acid is required for cysteine synthesis?
Methionine is what donates the sulfur group to synthesize cysteine.
So if methionine isn’t coming in the diet, cysteine will become an essential amino acid in the diet.
How is tyrosine synthesized?
What enzyme? what cofactor? what regenerates the cofactor?
What’s the substrate?
Tyrosine is formed by the hydroxylation by phenylalanine hydroxylase (PAH).
It takes phenylalanine and adds a hydroxyl group to the aromatic ring.
It uses BH4 as a cofactor, which is regenerated by Dihydropteridine reductates (oxidizing NADH)
What are the three general groups of intermediates that amino acids can be derived from and degrade into?
Glycolysis intermediates
TCA cycle intermediates
Acetyl CoA and Acetoacetate
What two main amino acids can be derived from glycolytic intermediates?
What additional AAs can be synthesized from these two glycolytic AAs?
Alanine (from pyruvate)
Serine (from 3-phosphoglycerate)
Off of serine you can make glycine and cysteine.
What three amino acids can be derived from 3-phosphoglycerate generated in glycolysis?
Serine first,
then glycine and cysteine
What amino acid is generated from pyruvate?
alanine
What glycolysis intermediate will serine break down to?
2-Phosphoglycerate
which is one step further down than the 3-phosphoglycerate that was used to synthesize serine
How is glycine synthesized? From what two possible amino acids? With what cofactor?
Glycine can be synthesized from serine using serine hydrosymethyl transferase and PLP and FH4 as cofactors.
Glycine can also be synthesized from threonine through beta elimination.
How can glycine breakdown result in kidney stones/
If the glycine is broken down through an oxidation pathway, oxalate is a byproduct and can buildup and crystallize into kidney stones if not excreted.
What two amino acids are involved in the synthesis of cysteine?
Serine and methionine
What two products does cysteine degradation yield?
What are they used for?
CYstein degradation yields sulfuric acid which is used to lower the pH of urine and PAPS, which is an activated sulfate that will donate SH groups in other reactions–including onto the proteins for the cytosol like proteoglycans
What mutation will result in cystinuria?
What will this cause clinically?
A mutation in the amino acid carrier for cysteine (and other basic amino acids like lysine, arginine and ornithine). THis makes cystein build up in the tubules of the kidney because it can’t be reabsorbed back into the blood.
This will result in kidney stones
What AA donates a nitrogen to pyruvate for yield alanine?
What enzyme is required?
Glutamate is the donor of the nitrogen,
Alanine Aminotransferase is the enzyme. (ALT)
What type of cell is alanine aminotransferase (ALT) expressed in?
What does having elevated ALT in the blood mean?
ALT is normally expressed only in hepatocytes.
ALT in the blood is an indicator of liver damage.
What 6 amino acids can be derived from TCA cycle intermediates?
Which two come off the TCA cycle immediately? Which 4 come off from those 2?
Aspartate is synthesized from oxaloacetate.
Glutamate can be synthesized from alpha-KG.
Asparagine is synthesized from aspartate
Proline, Arginine, and Glutamine are synthesized from glutamate
What two amino acids can you synthesize from oxaloacetate?
Aspartate and asparagine
What 4 amino acids can you synthesize from alpha-KG?
Glutamate
Glutamine
Arginine
Proline
THrough what two mechanisms can glutamate by synthesized?
- THrough glutamate dehydrogenase acting on alpha-KG.
- Through aspartate aminotransferase (AST) acting on aspartate (remember this removes the nitrogen from aspartate and puts it on alpha-KG to yield glutamate and oxaloacetate)
What enzyme converts glutamate to glutamine?
What enzyme converts glutamine back to glutamate?
Conversion of glutamate to glutamine requires glutamine synthetase
THe reverse reaction of glutamine to glutamate requires Glutaminase
What AA is used to generate proline?
What other amino acid can be synthesized if one of the intermediates form this reaction further becomes a substrate for the urea cycle?
Glutamate can be turned to a form that will spontaneously cyclize, resulting in proline.
If the glutamate semialdehyde goes off in another direction, it can synthesize ornithine, a urea cycle substrate to make arginine.
When branched chain amino acids are de-aminated, what is the result?
alpha-keto acids
WHen you get the deamination of branched chain amino acids, alpha keto acids are the result.
What happens to the alpha keto acids? THrough what enzyme?
THe a-keto acids are then decarboxylated and bound to CoA by a dehydrogenase complex which is very similar to PDH.
What are the three branched chain amino acids?
Valine, Isleoleucine, and Leucine
If there is an inherited defect in the alpha-keto acid dehydrogenase complex, what builds up? WHat is this disease called?
The branched alpha keto acids will build up, spilling over into the urine.
This is called Maple Syrup Urine DIsease (MSUD)
What are the classic symptoms of MSUD?
Presents in infants within 1 week of age
Convulsions, vomitting, maple syrup odor in urine
labs would show: elevated plasma and urine valine, isoleucine, leucine and ketoacids. Often with hypoglycemia, often with ketoacidosis
Treat acutely with hydration and transfusion
Treat long term with a synthetic diet low in BCAA
What characterizes the mild and intermittent versions of MSUD?
The classic is fatal if untreated, but intermittent and mild are survivable even without treatment.
For intermittent, the patient has alpha keto acid dehydrogrnase, but it’s less functional, so after unusually high protein meals you might get an episodic bout of neurological findings due to the ketoacid buildup in the blod,
THe mild version is associated with mild MR
What vitamine is given in high doses to treat people with intermittent and mild MSUD?
Thiamine because it’s the precursor to TPP, which is the cofactor for the E1 subunit of the alpha keto acid dehydrogrnase complex, which is usually the part that’s mutated.
This helps the dehydrogrnase complex to be more functional
Someone with high levels of branched chain amino acids in the blood have what disease?
People with unusually low levels of branched chain amino acids in the blood have what disease?
High BCAA = Maple Syrup Urine DIsease
Low BCAAs = a knockout of the branched chain amino acid dehydrogenase KINASE…so the dehydrogenase complex is never turned off and BCAAs are inapprpriately depleted.
What enzyme will turn off the branched chain alpha keto acid dehydrogenase complex?
the branched chain alpha keto acid dehydrogenase kinase!
This phosphorylates it, turns it off.
Knockouts of this result in autism, cognitive delay and seizures.
BCAAs would be very low in the blood
How do you alleviate symptoms of autism in patients who have a defect in their branched chain keto acid dehydrogenase kinase?
You supplement their diet with BCAAs
What are phenylalanine and tyrosine broken down to?
Fumarate (TCA cycle intermediate)
Acetoacetate (Ketone body)
What four disorders can arise from defects in the degradation of phenylalanine and tyrosine to fumarate and acetoacetate?
Phenylketonuria (PKU)
Tyrosinemia I and II
Alcaptonuria
What causes phenylkeotnuria?
Defect in phenylalanine hydrosylase which prevents tyrosine biosynthesis from phenylalanine
This causes an increase in phenylalanine in the brain and blood. Tyrosine becomes an essential amino acid
Symptoms include seizures, cognitid delay, light complexion, and a MOUSY ODOR
All infants are screened for blood phenylalanine and tyrosine concentrations at birth
Treat with a phenylalanine restricted diet.
A defect in what enzyme will mimic PKU symotoms?
A defect in the dihydropteridine reductase enzyme, which is was regenerates the BH4 cofactor required in the syntehsis of tyrosine form phenylalanine
What causes Tyrosinemia Type II?
What are the symptoms?
Mutation in Tyrosine aminotransferase (this is the reaction that removes the nitrogen from tyrosine in its degradation.
This means tyrosine builds up in the body.
Patients develop plaques on the hands and feet, corneal ulcers, and MR
Treat with a synthetic diet which is low in both phenylalanine and tyrosine.
What causes Alcaptonuria?
Deficiency in homogentisate oxidase which is the enzyme converts homogentisate to gumarate and acetoacetate in the degradation of phenylalanine and tyrosine.
It causes a buildup on homogentisic acid in the body (which can be detected in the urine)
Patients are asymptomatic until middle age, when they develop arthritis, back pain, renal calculi, dark urine, dark spots in eyes, and dark spots in ear cartilage
What causes tyrosinemia type 1?
It’s an inherited disorder of fumaryloacetoacetate hydrolase (FAH) which results in an accumulation of succinylacetone
Succinylacetone is toxic to liver cells, so patients present with acute hepatic crisis, usually at 2-4 months of age with jaundice, hepatomeagly, elevated AST and ALT, and hypoglycemia.
Diagnose with succinylacetone inurine and blood.
What is given to treat tyrosinemia type 1?
Nitosinone
Inhibits the production of homogentisic acid.
If you stop the production of homogentisic acid, then you don’t get the buildup of succinylacetone and you don’t get liver failure.
