Aa Degradation & Urea Cycle Ii

Front 1

What is the purpose of the urea cycle?

Back 1

To get the nitrogen from AA degradation out of the body (it's toxic otherwise).

Front 2

Where does the urea cycle occur?

Back 2

In liver - cytosol and mitochondria

Front 3

In what form is Ammonia transported to liver from extrahepatic tissues?

Back 3

By 4 transport amino acids:
-Gln, Ala, Ser, Arg.

Front 4

How is free intestinal ammonia delivered to the liver?

Back 4

Via the hepatic portal vein

Front 5

What happens to urea after its synthesis?

Back 5

Released into blood and sent to kidney for excretion.

Front 6

3 ways to get NH4+ into Liver Cytosol:

Back 6

1. Extrahepatic tissues send glutamine (2 NH4 groups)
2. Liver AAs give NH3 to a-KG -> Glu (aminotransferase)
3. Muscle sends Alanine; gives NH3 to a-KG -> Glu + Pyruvate

Front 7

Enzyme that converts Glutamine to Glutamate Gln in liver mitochondria:
What is needed?
What is produced?

Back 7

Glutaminase
-Needs H2O
-Produces NH4+ and Glutamate

Front 8

What happens to Glutamate in liver mitochondria?

Back 8

Conversion to a-ketoglutarate

Front 9

What enzyme catalyzes Glutamate -> a-KG in liver?

Back 9

Glutamate dehydrogenase

Front 10

What is special and unique about Glutamate dehydrogenase?

Back 10

It can use either NAD or NADP

Front 11

What regulates the activity of Glutamate Dehydrogenase?

Back 11

Energy levels:
-ADP/GDP activate NH3 release
-ATP/GTP inhibit it.

Front 12

What is free NH4+ in mitochondria used for?

Back 12

Urea synthesis

Front 13

What is the first step of urea synthesis?

Back 13

Synthesis of Carbamoyl Phosphate

Front 14

What enzyme accomplishes step 1?

Back 14

Carbamoyl Phosphate Synthetase

Front 15

So what do you know by the term Synthetase?

Back 15

It requires 2 ATP

Front 16

What is required to activate Carbamoyl Phosphate Synthetase?

Back 16

N-acetylglutamate

Front 17

What makes N-acetylglutamate?
What activates it?

Back 17

Acetylglutamate Synthase (does not require ATP) -> activated by Arginine from Urea cycle

Front 18

What are the substrates for making Carbamoyl Phosphate?

Back 18

-NH3 (from glu/gln)
-HCO3- (from respiration)
-ATP (2)

Front 19

What is the real first step of the urea cycle?

Back 19

Synthesis of Citrulline

Front 20

What is citrulline made from?

Back 20

Carbamoyl Phosphate + Ornithine

Front 21

How does Ornithine get into the mitochondrial matrix?

Back 21

Via a specific transporter

Front 22

How does Citrulline get out of the mito matrix?

Back 22

By another specific transporter

Front 23

What enzyme makes Citrulline?

Back 23

Ornithine Transcarbamoylase

Front 24

Any requirements for this first step?

Back 24

Nope; just releases a phosphate.

Front 25

What is involved in the 2nd step in Urea cycle?

Back 25

2 reactions, one intermediate

Front 26

What is step 2a of urea cycle?

Back 26

Citrulline + ATP makes an activated Citrullyl-AMP intermediate

Front 27

What enzyme catalyzes steps 2a/2b?

Back 27

Argininosuccinate Synthetase

Front 28

What does the name synthetase tell you right away?

Back 28

It will use ATP

Front 29

What happens to the Citrullyl-AMP intermediate?

Back 29

AMP gets replaced by Aspartate to make Argininosuccinate.

Front 30

Where does the Aspartate come from?

Back 30

Oxaloacetate shuttling in the mitochondria during the TCA cycle.

Front 31

What enzyme acts on Argininosuccinate? What does it produce?

Back 31

Argininosuccinate Lyase; produces Fumurate and Arginine

Front 32

Where does Aspartate in the liver mitochondria come from again?

Back 32

-Fed state: from OAA in TCA.
-Starving: from Alanine -> OAA -> THEN to Aspartate.

Front 33

So what happens to the Citrullyl-AMP intermediate?

Back 33

It combines with Asp to make Argininosuccinate, w/ release of AMP.

Front 34

And what happens to Argininosuccinate?

Back 34

Argininosuccinate Lyase cleaves it into Fumarate + Arginine

Front 35

What is the other product of Argininosuccinate Lyase?

Back 35

Arginine

Front 36

What happens to the Arginine produced in step 3 of urea cycle?

Back 36

It has 2 Options:
-Go to TCA cycle
-Continue in the Urea cycle

Front 37

What acts on Arginine in step 4 of the urea cycle? Products?

Back 37

Arginase - makes Urea and Ornithine

Front 38

What does Urea do after release from Arginine?

Back 38

The blood transports it from liver to kidney for excretion.

Front 39

What happens to the ornithine produced by arginase?

Back 39

It goes back to Mitosol for re-entry into the cycle.

Front 40

What happens to some of the newly made urea?

Back 40

Goes back into the intestine (via diffusion) and cleaves to CO2 + Ammonia

Front 41

What enzyme causes intestinal cleavage of ammonia?

Back 41

Urease in intestinal bacteria.

Front 42

How do the intermediates in the urea cycle get to the next enzyme?

Back 42

They are directly channeled from one active site to the next.

Front 43

How many ATP are used in the urea cycle?

Back 43

3

Front 44

What substrates are used by the urea cycle (total)?

Back 44

1 NH4+
1 HCO3-
3 ATP
1 H2O
1 Aspartate

Front 45

What products are given off by the urea cycle (total)?

Back 45

1 Urea
2 ADP
2 Pi
1 AMP
1 PPi
1 Fumarate

Front 46

What are the most direct sources of ammonia for the urea cycle?

Back 46

-Free ammonia
-Aspartate

Front 47

What shunt links the TCA and Urea cycles?

Back 47

Aspartate:Argininosuccinate Shunt

Front 48

Why is ALANINE the source of ASPARTATE during starving, exercise, or diabetes crisis?

Back 48

B/c the TCA cycle is not running to make OAA; have to get it some other way.

Front 49

What are the 2 types of regulating the Urea cycle?

Back 49

1. Availability of N-acetylglutamate to activate Carbamoyl Phosphate synthetase
2. Enzyme transcription

Front 50

What happens to the urea cycle in starving people or those on hi-protein diets?

Back 50

It goes unregulated to detoxify all the amino acid breakdown products.

Front 51

How are extrahepatic tissues detoxified of ammonia?

Back 51

By synthesis of AGGS:
Ala, Glu, Gln, Ser

Front 52

What happens to AGGS?

Back 52

Released to bloodstream, taken to liver, for Urea cycle.

Front 53

What happens when ammonia levels are excessively high?

Back 53

The tissues are depleted of Glutamate and a-KetoGlutarate as Glutamine is synthesized for NH3 transport.

Front 54

Why are high levels of Glutamine and NH3 toxic?

Back 54

They cause the brain to swell.

Front 55

What are the amino acid neurotransmitters?

Back 55

GABA and Glutamate

Front 56

What enzyme defcncy would be indicated by LOW Citrulline levels and excess Carbamoyl Phosphate levels?

Back 56

Ornithine Transcarbamylase

Front 57

What is the treatment for this inborn error of metabolism?

Back 57

Liver transplant

Front 58

What are Sodium Benzoate and Sodium Phenylacetate?

Back 58

Nitrogen waste medications

Front 59

What is the mechanistic basis for nitrogen waste meds?

Back 59

Benzoate and Phenylacetate form complexes with AA's and allow their excretion.

Front 60

What makes Ornithine transcarbamoylase deficiency unique from all other urea cycle enzyme deficiencies?

Back 60

It is X-linked (less severe in women)

Front 61

How is Argininosuccinate Lyase deficiency treated?

Back 61

by giving dietary Arginine.

Front 62

Why is dietary Arginine sufficient for treating Argininosuccinate lyase defic?

Back 62

B/c Argininosuccinate can be excreted - don't HAVE to break it down all the way to urea.

Front 63

If Argininosuccinate can be excreted, why give arginine?

Back 63

Because you have to keep the urea cycle going by regenerating Ornithine.

Front 64

What major organ disease can lead to impaired urea synthesis?

Back 64

Reyes disease - or any liver damage - this is the site of urea cycle.