Ammino Acid Metabolism Lecture Sep 5

Question 1

What are the three cofactors for enzymes in amino acid metabolism?

What are their purposes?

Answer 1

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

Question 2

What nine amino acids are considered essential in the diet? Why do they need to come from the diet?

Answer 2

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

Question 3

What essential amino acid does tyrosin require for syntehsis?

Answer 3

phenylalanine.

So if phenylalanine is low, then tyrosine becomes an essential amino aicd in the diet because it cannot be synthesized

Question 4

What essential amino acid is required for cysteine synthesis?

Answer 4

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.

Question 5

How is tyrosine synthesized?

What enzyme? what cofactor? what regenerates the cofactor?

What’s the substrate?

Answer 5

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)

Question 6

What are the three general groups of intermediates that amino acids can be derived from and degrade into?

Answer 6

Glycolysis intermediates

TCA cycle intermediates

Acetyl CoA and Acetoacetate

Question 7

What two main amino acids can be derived from glycolytic intermediates?

What additional AAs can be synthesized from these two glycolytic AAs?

Answer 7

Alanine (from pyruvate)

Serine (from 3-phosphoglycerate)

Off of serine you can make glycine and cysteine.

Question 8

What three amino acids can be derived from 3-phosphoglycerate generated in glycolysis?

Answer 8

Serine first,

then glycine and cysteine

Question 9

What amino acid is generated from pyruvate?

Answer 9

alanine

Question 10

What glycolysis intermediate will serine break down to?

Answer 10

2-Phosphoglycerate

which is one step further down than the 3-phosphoglycerate that was used to synthesize serine

Question 11

How is glycine synthesized? From what two possible amino acids? With what cofactor?

Answer 11

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.

Question 12

How can glycine breakdown result in kidney stones/

Answer 12

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.

Question 13

What two amino acids are involved in the synthesis of cysteine?

Answer 13

Serine and methionine

Question 14

What two products does cysteine degradation yield?

What are they used for?

Answer 14

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

Question 15

What mutation will result in cystinuria?

What will this cause clinically?

Answer 15

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

Question 16

What AA donates a nitrogen to pyruvate for yield alanine?

What enzyme is required?

Answer 16

Glutamate is the donor of the nitrogen,

Alanine Aminotransferase is the enzyme. (ALT)

Question 17

What type of cell is alanine aminotransferase (ALT) expressed in?

What does having elevated ALT in the blood mean?

Answer 17

ALT is normally expressed only in hepatocytes.

ALT in the blood is an indicator of liver damage.

Question 18

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?

Answer 18

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

Question 19

What two amino acids can you synthesize from oxaloacetate?

Answer 19

Aspartate and asparagine

Question 20

What 4 amino acids can you synthesize from alpha-KG?

Answer 20

Glutamate

Glutamine

Arginine

Proline

Question 21

THrough what two mechanisms can glutamate by synthesized?

Answer 21

1. THrough glutamate dehydrogenase acting on alpha-KG.
2. 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)

Question 22

What enzyme converts glutamate to glutamine?

What enzyme converts glutamine back to glutamate?

Answer 22

Conversion of glutamate to glutamine requires glutamine synthetase

THe reverse reaction of glutamine to glutamate requires Glutaminase

Question 23

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?

Answer 23

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.

Question 24

When branched chain amino acids are de-aminated, what is the result?

Answer 24

alpha-keto acids

Question 25

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?

Answer 25

THe a-keto acids are then decarboxylated and bound to CoA by a dehydrogenase complex which is very similar to PDH.

Question 26

What are the three branched chain amino acids?

Answer 26

Valine, Isleoleucine, and Leucine

Question 27

If there is an inherited defect in the alpha-keto acid dehydrogenase complex, what builds up? WHat is this disease called?

Answer 27

The branched alpha keto acids will build up, spilling over into the urine.

This is called Maple Syrup Urine DIsease (MSUD)

Question 28

What are the classic symptoms of MSUD?

Answer 28

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

Question 29

What characterizes the mild and intermittent versions of MSUD?

Answer 29

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

Question 30

What vitamine is given in high doses to treat people with intermittent and mild MSUD?

Answer 30

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

Question 31

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?

Answer 31

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.

Question 32

What enzyme will turn off the branched chain alpha keto acid dehydrogenase complex?

Answer 32

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

Question 33

How do you alleviate symptoms of autism in patients who have a defect in their branched chain keto acid dehydrogenase kinase?

Answer 33

You supplement their diet with BCAAs

Question 34

What are phenylalanine and tyrosine broken down to?

Answer 34

Fumarate (TCA cycle intermediate)

Acetoacetate (Ketone body)

Question 35

What four disorders can arise from defects in the degradation of phenylalanine and tyrosine to fumarate and acetoacetate?

Answer 35

Phenylketonuria (PKU)

Tyrosinemia I and II

Alcaptonuria

Question 36

What causes phenylkeotnuria?

Answer 36

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.

Question 37

A defect in what enzyme will mimic PKU symotoms?

Answer 37

A defect in the dihydropteridine reductase enzyme, which is was regenerates the BH4 cofactor required in the syntehsis of tyrosine form phenylalanine

Question 38

What causes Tyrosinemia Type II?

What are the symptoms?

Answer 38

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.

Question 39

What causes Alcaptonuria?

Answer 39

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

Question 40

What causes tyrosinemia type 1?

Answer 40

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.

Question 41

What is given to treat tyrosinemia type 1?

Answer 41

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.