Biochemistry: Urea Cycle

Excess amino acids are used for

synthesis of new proteins OR converted to common metabolites for other cellular uses

First step (to use aa for anuything other than making proteins) is

removal of amino group

transamination

transfer of an amino group from an amino acid to an a-ketp acid

transamination forms

the original amino acid loses its amine group and becomes and alpha keto acid

the origingal alpha keto acids gains the amine group and becomes a new amono acid

alpha ketoglutarate is often the amino acceptors generating

glutamate

We want to make sure we get alpha ketoglutarate back so a second reaction

glutamate reacts with oxalacetate

oxalacetate takes the amine group and generates aspartatee

this regenerates alpha keotglutatare

what enzyme does this transfer of amino groups

aminotransferases (transaminoases)

we have about 20 (one for each aa)

aminotransferases have a

specific site for the amono acid donating the amino acid

most aminotransferases only accept

a-ketoglutarate or oxaloacetate as the acceptor

( we make a lot of glutamate or aspartate)

aminotransferases use ____ as a cofactor

Vitamin B6- pyridoxine

Lots of transaminase reactions are done in

the liver!

Deamination

the removal of an amino group from an organism, particularly from an amino acid

Glutamate is deaminated by

glutamate dehydrogenase

this forms

alpha ketoglutarate

and form NADPH and ammonia

during deamination we have an increase in ____ levels in the blood

ammonia

Ammonia at high levels

Toxic to brain - mental impairment and lethargy

the body tries to put the amino group back on tho alpha keotglutarate , thus a-ketoglutarte levels go down, and tCA cycle goes down

neuronal death due to decreased TCA since a-ketoglutarate levels are depleted to detoxify high amonia levels

Aquatic organisms eliminate ammonia by

excrete ammonia

birds and reptiles elinate ammonia by

uric acid

terrestrial organisms eliminate ammonia by

producing urea

Urea Cycle

5 enzymatic reactions

2 mitochondrial + 3 cytosolic

Urea formula

CO(NH2)2

1 nitrogen group comes from ammonia

1 nitrogen group comes from aspartate

Carbon comes from bicarbonate

What are the reactants of Urea Cycle.

ammonia

aspartate

bicarbonate

What are the prodcuts of Urea Cycle.

Urea

Fumarate (TCA)

Urea cycle is an energy _____ process

using !

3 ATP

Reaction 1 is done by

Carbamoyl phosphate synthetase (CPS)

Reaction 1 is

irreversible!

rate limiting step

control step

uses 2 atp

Reaction 2 is done by

ornithine transcarboamoylase

ornithine transcarboamoylase

transferes carbamoyl from carbamoyl phosphate to ornithine to yield citrulline

ornithine and citrulline are

non standard amino acids

citrulline must be created so

the reaction leaves the mitochondria

it can leave but can not enter back in

reaction 3 is done by

arginiosuccinate synthetase

arginiosuccinate synthetase

an aspartic acid is added to citrulline to form arginosuccinate

uses ATP

arginosuccinate is also a

non standard amino acid

reaction 4

argininosuccinase

Argininosuccinase

fumarate is eliminated from arginosuccinate leaving arginine

reaction 5

arginase

arginase

arginine is hydrolyzed to yield urea and regenerate ornithine

Energy spent is recovered in the

oxidation of the carbon skeletons left after deamination

fumarate goes to TCA etc

REGULATION

what step is most regulated

Which TCA cycle enzyme will use a urea cycle product

fumarase

Where is urea produced

liver, kidnet filters urea out of the blood into the urine

high blood NH3

liver disease

high blood urea

kidney disease

Nitrogen balance in normal individuals

nitrogen in = nitrogen out

positive nitrogen balance

growing children or trauma recovery

nitrogen in > nitrogen excreted

we need the amino acids we eat

Negative nitrgen balance

malnourished

nitrogen in < nitrogen out

nitrogen out is coming from your own proteins

what percent of energy should come from oxidative breakdown of amino acids

10-15 %

we want these aa to make new things not break down

Glucogenic amino acids

amino acids are degraded to pyruvate, a-ketoglutarate, succinyl-CoA, fumarate, or oxalacetate

THESE ARE GLUCOSE PRECURSORS

ketogenic amino acids

broken down to acetyl-CoA or acetoacetate and can be converted to fatty acids or ketone bodies

What are the 5 amino acids are both glucogenic and ketogenic amino acods

isoleucine

phenylalanine

threonine

tryptophan

tyrosine

All amino acids must be _______ before they can be used as other untermediates

deaminated

Tyrosine can be used to make

melanin - skin and hair pigment

dopamine - neurotransmitter

norepinephrine - fight or flight

epinephrine- fight or flight

Tryptophan used to make

serotonin - sleepy/happy

niacin B3

Glutamate used to make

gamma -Aminobutyric acid GABA

neurotransmitter

Histidine is used to make

histamine

Phenylketonuria (PKU)

deficiency of phenylalanine hydroxylase (autosomal recessive)

phenylanine can not be converted to tyrosine

phenylpyrivate and phenyllactate produced instead (VERY ACIDIC)

intellectual disabilities, very light skin (can not make melanin), increased seizures

in CHILDREN

tested at birth

phenylketonuria treatment

early detection

low phenylaline diet (need some to make protein)

supplementation with tyrosine

Aspartame contains

phenylaline

Alkaptonuria (Black Urine Disease)

deficiency of HG (autosomal)

accumulates HG in blood that is then excreted in the urine

oxidized = black (this is not harmful)

deposits in cartilage lead to arthritis

Alkaptonuria Treatment

No treatment

restrict diet of Phe and Tyr

Vitamin C - natural antioxidant (makes urine not black)

Nitisnone (herbicide) can block enzyme involved in synthesis of HG acid but side effects include cornea irritation

Cystinuria

reduction in intestinal absorption and proximal tubular reabsorption of dibasic amino acids (transporter malfunction) (autosomal recessive)

cysteine is not reabsorbed and will oxidize to cystine

cystine is insoluble and will form kidney stones

Cystinuria treatment

restrict diet of cysteine and methionine

(methionine is converted to cysteine)

Maple Syrup Urine Disease

Deficiency in branched-chain alpha-keto acid dehydrogenase complex (autosomal)

increase in branched chain amino acids (isoleucine, leucine, valine)

leads to production of Sotolon = has a distinctive maple syrup odor

Maple Syrup Urine Disease Treatment

Dietary Restriction of amino acids

ketogenic

- leucine, lysine

Glucogenic

- alanine, cystein, cystine, glutamine

Both

- isoleucine, phenylaline, threaonione, tyrptophan, tyrosine

MSUD

you miss diagnose someone with amino acid metabolism disorder and put them on tyrosine retricted diet. Which disorder would be most aggravted by this miss diagnosis and treatment regime?

PKU