GOALS

TUTORIAL SLIDES

Amino acid catabolism: nitrogen metabolism

l. Remove the amino group
2. Dispose of nitrogen via ___
3. Degrade carbon to metabolic products

Amino group is removed by transamination or oxidative deamination.

Must transport to the liver to make urea. Amino group is transported via blood as ___ or ____.

In the liver, alanine and glutamine are converted into ____.

Glutamate is converted to ___ and ______ by glutamate dehydrogenase.

___ is used to make urea.

The carbon skeletons of the amino acids are degraded either to acetyl-CoA or to pyruvate or citric acid cycle intermediates.

Production of urea

In liver mitochondria, NH4+ reacts with HC03- & ATP to make ___ _____. (Catalyzed by ____ ____ synthetase I)

Carbamoyl phosphate combines with ornithine to make ____, which is transported to the cytoplasm.

____ provides the second nitrogen that will become urea.

____ is the penultimate product.

___ cleaves arginine to generate ___ and ornithine. Ornithine is recycled through the path.

Urea is ____

Urea

1 nitrogen is from ____,
incorporated from carbamoyl phosphate

The carbon is from ____, incorporated from carbamoyl phosphate

1 nitrogen is from ____

Amino acid catabolism

Amino acid catabolism produces ___ skeletons that are metabolized

Defects in carbon skeleton metabolism underlie some ____

Amino acid catabolism releases ____

Ammonia accumulation is ___, therefore management of nitrogen waste is critical

Nitrogen from amino acid catabolism is eliminated via the ___ ___

Nitrogen-containing waste products

Two major nitrogen-containing waste
products that are excreted

1) ___ — produced in the liver from ammonia

2) __ ___ produced
during purine catabolism

Amino GROUP metabolism

most amino acids degraded in ____

excess ammonia from other tissues is transported as amino acids
(___ or ___) to the liver

in liver excess ammonia is converted to ____

4 amino acids are key for nitrogen metabolism — ___, ___, ____, & ___

Recall - Removal of nitrogen

For amino acids catabolized in the liver:
Amino group from amino acid is removed via a ____ reaction

Generally, keto acid acceptor is _____: produces glutamate, which is transported into the mitochondria

In mitochondria, glutamate is oxidized to a-ketoglutarate and ___

Enzyme is glutamate ____ — seen before — rxn runs in reverse here

___ is produced, which is used for ETC and production of ATP

Transporting nitrogen to the liver

In MUSCLE:
α-ketoglutarate + amino acid ⇌ glutamate + α-keto acid,

Then:
pyruvate + glutamate ⇌ alanine + α-ketoglutarate

____ is transported in blood to liver

In OTHER tissues, NH4(+) is released from glutamate by ___ deamination.

Then:
NH4(+) + glutamate + ATP ⇌ glutamine + ADP + Pi

Catalyzed by ____ _____

Glutamine is transported in blood to liver.

In the liver

Alanine from ___ — transamination reaction to transfer amino group to α-ketoglutarate generating ____ in the liver

Glutamine from other tissues - is converted to glutamate and NH4(+) by ____ (in mitochondria)

Glutamate is then converted to NH4(+) and α-ketoglutarate by ___ _____

NH4(+) is used to synthesize ___

Urea

less toxic than ____

uncharged

___-soluble

transported via the blood to ___ for excretion

"___" of urine

Overview of urea cycle

Ornithine plays an important role

Nitrogen in urea comes from 2
sources:
l) ____ ____ and 2) _____

Arginine is cleaved by ____
to regenerate ___ and produce urea

Synthesis of carbamoyl phosphate
'
recall — citric acid cycle generates CO2

recall — carbonic ___ catalyzes the formation of carbonic acid from C02 and H2O dissociates into bicarbonate and H+

a mitochondrial carbonic anhydrase produces ____

bicarbonate reacts with ___ and ATP to produce carbamoyl phosphate
catalyzed by __ ___ ___ __ in a reaction requiring 2 ATPs

Urea cycle - detail

carbamoyl group from carbamoyl phosphate is transferred to ornithine to produce ____ (mitochondria)

citrulline condenses with aspartate to generate ____ (cytoplasm)

arginosuccinate is cleaved to produce ___ & ____ (cytoplasm)

arginine is hydrolyzed by ___ to produce ___ & ___ (cytoplasm)

Urea cycle - detail

Carbamoyl phosphate and citrulline made in _____

subsequent steps in ____

Citrulline transported via the ___-____ ___

glutamate-aspartate ____ also important

Urea cycle

ornithine in the urea cycle is analogous to ____ in the citric acid cycle modified at each step of the cycle and ____ at the end of the cycle

Fumarate (made in cytoplasm) is hydrated to form ___— enters
mitochondria via malate-α-ketoglutarate exchanger and into citric acid cycle

Enzymes in urea cycle are clustered — products are channeled to next
enzyme without being ____

Relationship of urea and citric acid cycles

____ is produced in the urea cycle and enters the citric acid cycle

Oxaloacetate in the citric acid cycle can be
converted to ____ to be used in the urea cycle

Connection reduces the energy ___ of urea synthesis

Balance of urea cycle by flux

reactions catalyzed by glutamate dehydrogenase and the transaminase are ____

_____ aspartate and carbamoyl phosphate levels for urea production (so urea can always be made)

note how reactions proceed differently, depending on the molecule in ____

If ___ in excess, the urea cycle is favored

If ____ in excess, the citric acid cycle is favored

Control of Urea Cycle

Short term regulation:
carbamoyl phosphate synthetase I is allosterically ___ by N-acetylglutamate — produced when glutamate, acetyl CoA and arginine are ___

arginine activates N-acetylglutamate ___ which produces N-acetylglutamate from ___ & ___ ___

Long term regulation:
Expression of carbamoyl phosphate synthetase I and all enzymes in
urea cycle is regulated by __ & ___

Glutamine metabolism in the kidney produces ___ to buffer the blood

Ammonia is excreted in urine and ___ enters blood to replenish

Recap I

excess ammonia transported to liver as ___ or ___

glutaminase (glutamine) or transamination (alanine) produces ____

glutamate dehydrogenase releases ____ in mitochondria

carbamoyl synthetase I produces ___ ___ from bicarbonate, ammonia and ATP

carbamoyl group is transferred to ornithine to produce ___

aspartate condenses with citrulline and the product is cleaved to produce ____ and ____ (to citric acid cycle — via malate)

arginine is cleaved by ____ to produce ornithine and urea

Recap II

some reactions of the urea cycle in mitochondria and some in the cytoplasm

short term regulation by ___ mechanism, long term regulation
by altering ___ levels of enzymes