Lecture 36 - Protein breakdown and Urea formation Flashcards Preview

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Flashcards in Lecture 36 - Protein breakdown and Urea formation Deck (18):
1

Equation that applies to all aspects of the body

Growth = Synthesis - Breakdown

2

Nitrogen balance (5)

Proteins taken in by diet, no speciifc protein stores in our body. Dietary protein broken down into aa, number of fates for these aa.
Proteins can be structural/functional.
Generally there should be a balance between input and output.
Positive nitrogen balance.
Negative nitrogen balance.
In nitrogen balance breakdown = synthesis. e.g. 100g output a day = 100g input a day.

3

Nitrogen balance - Positive (4)

Amount of protein we retain exceeds the amount that is broken down and excreted. Normal process and occurs in things like growth.
Physiological reasons e.g. small child or when someone is pregnant they will be taking in/laying down more protein.
In response to exercise --> tissue hypertrophy.
Response to anabolic hormones.

4

Nitrogen balance - Negative (4)

Input superseded by breakdown.
Due to protein deficiency.
Pathophysiology e.g. wasting diseases, burns and traumas can cause all of this.
Response to catabolic hormones (or a lack of anabolic hormones e.g. diabetes). Causing someone to lose body protein mass.

5

Metabolism of AA (2)

Body protein metabolism deals with AA in two parts. The nitrogen and carbon skeleton.
Nitrogen - Breaking down of protein/polypeptide via peptidases into its constituent aa.
Carbon skeleton - Used for energy metabolism or biosynthesis pathways.

6

Removal of nitrogen (5)

Nitrogen is toxic (adverse effect on neuronal cells) so has to be removed safely.
Converted to non-toxic urea and excreted in the urine.
3 step process - Transamination, Formation of ammonia, Formation of urea.
Urea cannot be formed in muscle as the enzyme is not present, the carbon skeleton can be obtained and used for energy.
Urea contains 48% of nitrogen by weight, protein contain 16%, therefore 1 g of urea is formed from 3g of protein.

7

STEP 1: Transamination (9)

Occurs in cytosol.
Nitrogen as part of the α-amino group is transferred to an α-keto-acid to become a new amino acid.
α-ketoglutarate, pyruvate and oxaloacetate are α-keto acids. Can be oxidised/converted to make glucose (gluconeogenesis).
The enzymes that do this are transaminases, there are different types.
Transaminases are primarily liver enzymes, so can be used diagnostically, high levels are indicative of liver damage (as they SHOULD NOT be found in plasma.
Most important are the alanine (ALT) and aspartate (AST) transaminases.
• ALT allows (equilibrium towards RHS) - Requires vitamin B6.
Alanine + α-ketoglutarate pyruvate and glutamate
• AST allows (equilibrium towards LHS)
Aspartate + α-ketoglutarate Oxaloacetate and glutamate
Both reactions are fully reversible.
Glutamate transports potentially toxic nitrogen.

8

STEP 2: Formation of Ammonia (5)

Glutamate can release ammonia by a second enzyme, glutamate dehydrogenase (present in mitochondrial matrix) ---> a-ketogluterate.

Fully reversible and NAD (degradation) /NADH (synthesis) is used.
Other aa transfer their alpha amino group (NH3) to alpha ketoglutarate. Called oxidative deamination.

Glutamate is freely interchangeable with the a-keto acids as well as the ability to donate/accept ammonium ions.

Important as allows aa --> glutamate, which is transported and re-converted back into something the body can use for energy, while resynthesising the ammonia which can be fed into the urea cycle.

9

STEP 3: Elimination of Free Ammonia (4)

Glutamate + NH4+ + ATP Glutamine + ADP [Glutamine synthase]
Takes place in the periphery.
Glutamine synthase is widely distributed, esp. in blood vessels (esp in liver) with a lot of protein breakdown.
Reaction goes both ways so we can resynthesise the glutamate from the glutamine.

10

Urea cycle (9)

Non-toxic/Soluble compound, readily excreted.
Metabolic pathway used to excrete nitrogen.
Restricted in distribution, predominantly in liver - takes place in the mitochondria and cytoplasm of hepatocytes.
Urea cycle uses these substrates bicarbonate, aspartate and ammonium ions (released from glutamine/glutamate).
Bicarbonate = Break down of carbon skeleton (i.e. CO2, as a byproduct of metabolising the carbon skeleton, forms bicarbonate which will be used to obtain CO2 needed).

Urea: OC(NH2)2.
Two nitrogen atoms (one from aspartate, other from glutamine/glutamate).
C=O from carbon skeleton, through using CO2 that has been produced from its breakdown.
Products of aa degradation can be combined to form urea.
Urea and TCA cycle linked.

11

Urea cycle process - Diagram

Diagram

12

Urea cycle - Muscle (6)

Does not have enzymes to form urea, so doesn't have urea cycle.
Muscle does breakdown amino acids during prolonged exercise/starvation.

Branched aa are used for this energy (e.g. leucine).

Two routes by which aa are dealt with:
Nitrogen transferred to alanine via glutamate and pyruvate.
Circulating/Intracellular glutamate --> glutamine
(return to liver).

Muscle can export alanine (major exports that is actively broken down- in exercise/starvation).

13

Glucose alanine cycle - Diagram

Diagram

14

Transport of ammonia from peripheral tissue to the liver - Diagram

Diagram

15

Fate of carbon skeleton (7)

Carbon skeleton can be used for the production of glucose, ketone bodies and/or energy.
Ketogenic aa form ketone bodies.
Glucogenic aa form glucose (in the liver).
Some aa in both categories.
aa feed into different parts of the main carbohydrate pathway.
Occurs in the liver where most gluconeogenic pathways take place.
aa broken down can be converted into intermediates of the TCA cycle, which means we can convert it back to glucose.

16

Protein and AA Metabolism - After a meal (3)

Normal individual: High insulin, Low glucagon
Most aa from a protein meal will be used for protein synthesis in peripheral tissues such as skeletal muscle.
Excess aa can be used as sources of energy, and the N derived from their oxidation will be incorporated in the liver/excreted.

17

Protein and AA Metabolism - During starvation (3)

Normal individual : Low insulin, High glucagon
Short-term: Net flow of aa from muscle to liver. Increased production of glucose and urea.
Long-term: Tissue protein is "spared" because ketone bodies replace glucose as a major energy source fuel for the brain.

18

Protein and AA Metabolism - Untreated diabetes (4)

Negative nitrogen balance associated with short-term starvation persists even though subject is fed, leading to muscle wasting.
-ve balance due to decreased protein synthesis/ increased protein breakdown.
Seen in conditions of chronic infections , late stage cancer or trauma, including that following surgery or burns injury.
Some of these effects are mediated by cytokines.