BCH 3066/ METABOLISM OF NITROGEN COMPOUNDS: METABOLISM OF ACIDS

AMINES

General information on metabolism

Definitions

Metabolism is the set of material transformations and energy exchanges that take place in

living beings (animals, plants, etc.); it involves catabolism and anabolism.

Catabolism reactions are reactions during which there is degradation of macromolecules

into its subunits with energy release (∆G<0).

Anabolism reactions, on the other hand, are reactions during which there is synthesis of

macromolecules from subunits with energy consumption (∆G>0).

The starting point of the metabolism is the food intake called food. These foods

contain nutrients such as vitamins, mineral salts, carbohydrates, proteins, water,

lipids. If water, vitamins and mineral salts can be absorbed without transformation,

proteins, lipids and carbohydrates generally have to undergo transformations (digestion)

before being absorbed. This takes place in the digestive tract in specific sites involving enzymes
just as specific. At the end of digestion, we obtain nutrients that will be absorbed and

undigested products will pass through the large intestine to be eliminated in the faeces. Dependent on nature
of these nutrients they will be absorbed by simple diffusion (requiring neither energy nor carrier),

facilitated diffusion (involving a carrier but not energy) and/or active transport (which requires the energy

and a carrier). The nutrients thus absorbed must be distributed at the level of the different cells
to be used. This process is called nutrition, i.e. the replenishment or entry of nutrients into the

cellular level. It is therefore the enzymatic transformation that nutrients undergo at the cellular level
called metabolism.

Characteristics of metabolism

i- The metabolism is compartmentalized; each reaction takes place in a specific compartment in the
cell. There are therefore reactions that take place only in the mitochondria and not elsewhere. The

transamination for example takes place in the cytosol.

ii-The metabolism is highly regulated by various mechanisms. As an example, we have the regulation

allosteric which makes it possible to adjust the syntheses and degradations to the needs of the cell.

iii-The metabolism is highly integrated, that is to say, the products of the degradation of different

macromolecules give the same intermediate at the cellular level having the same destiny.

iv-The cell in which metabolism takes place operates on the principle of maximum economy in

time, space and energy.

Generally speaking, we all have macromolecules that degrade in different pathways

metabolic processes to provide acetyl CoA which enters the citric acid cycle to produce the

reduced coenzymes and ATP. These coenzymes will in turn integrate the chain to produce energy (ATP)
necessary for the functioning of the cell.

General scheme of transformation of macromolecules

   
 

 
 
  
 
 

Protein Metabolism

Once ingested, food proteins are chewed and undergo digestion, the first site of which
is the stomach which releases a proenzyme called pepsinogen which in turn gives the active pepsin. The

pepsin will in turn cleave proteins into amino acids and polypeptides.

Digestion continues at the level of the duodenum where the pancreas releases the pancreatic juice containing the

proenzymes trypsinogen, chymotrypsinogen, procarboxypeptidases. These proenzymes undergo

transformations to be active. Thereby,

Trypsinogen will give trypsin

Chymotrypsinogen will give chymotrypsin

Procarboxypeptidase will give carboxypeptidase A and B.

These enzymes will act on the polypeptides to release amino acids and oligopeptides. The digestion
oligopeptides ends at the level of the jejunum with the help of aminopeptidases which will hydrolyze them into

amino acids.

The products of digestion (amino acids) are absorbed then distributed to the cells to

use. The main function of amino acids is that of protein synthesis (plastic role). They
can also be broken down to provide energy to cells under specific conditions.

II- Amino acid metabolism.

A)- GENERAL.
Amino acids are both precursors and breakdown products of proteins. They play a role

capital in the development and maintenance of living matter; they come either from an endogenous synthesis,
either from food, or finally from the degradation or renewal of circulating proteins and

tissue.

Amino acids are mainly used as materials in the biosynthesis of proteins, but they can
undergo oxidative degradation in 3 different metabolic circumstances:

1- During the normal turnover of body proteins, the amino acids released, if they are not
not necessary for the synthesis of new body proteins, may undergo degradation

oxidative.
2- When the amino acids are ingested in excess compared to the needs of the human body for the

protein synthesis, the surplus can be catabolized with the release of ammonia since the acids

amines cannot be stored.

3- During fasting or diabetes mellitus when carbohydrates are either not available or incorrectly

used, the proteins are then used as fuel since there is no acid reserve
amino acids, the interrelationships with carbohydrate and lipid metabolism contribute to balancing the

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 amino nitrogen exchanges and adapt them to cellular needs. In fact, it is only during the diet,
when starch stores are depleted, the body begins to burn its own proteins ie

those of the muscles as fuel.

Amino acids are classified into two groups: essential amino acids and non-essential amino acids.

Mammals synthesize non-essential amino acids from metabolic precursors; by

against the essential amino acids also called indispensable must be provided, prefabricated in the
food ration.

B)- CATABOLISM OF AMINO ACIDS.

This is the catabolism of amino acids in the animal cell. This can be done either by:

- Oxidative deamination
- Other deamination mechanisms

- Decarboxylation

- Transamination.
1- Oxidative deamination:

All vertebrates excrete nitrogen in the form of urea (mammals), ammonia (fish) or acid
uric (birds, reptiles).

In the general scheme, amino acid catabolism begins with oxidative deamination. In

many organisms, there are several types of amino acid dehydrogenases, some of which
play only a minor role.

One is an acid-specific FMN (Flavin Mono Nucleotide) flavoprotein auto oxidase

amino acids in the L configuration, called L-amino acid oxidase.

H L-amino acid oxidase

COO -
H 2NOT VS COO -
     
O
     + NH 3
   
R E-FMN R
E-FMNH 2
L-amino acid α-keto acid

H 2O 2 O2

H 2O 2 H 2O + 1/2O 2
  Catalase

The participation of this enzyme in the general catabolism of amino acids can be considered as

negligible.

The other is an auto-oxidizable flavoprotein with FAD (Flavin Adenine Dinucleotide), specific for acids

amino acids in D configuration, called D-amino acid oxidase. This enzyme is very active, although its

substrates (D-amino acid) are not found under natural conditions.

H D-amino acid oxidase -

H 2NOT VS COO -
O COO + NH 3
          
   
R E-FAD R
E-FADH 2
D-amino acid α-keto acid

H 2O 2 O2
H 2O 2 H 2O + 1/2O 2
  Catalase

Monoamine oxidases (MAOs) are the flavoproteins of the intestine, liver, kidneys and many
other organs that catalyze the oxidative deamination of aromatic amines in food

or the products of digestion. They prevent the penetration of these vasoconstrictor or toxic amines into

the body like tyramine. Monoamine oxidases are also present in the nervous system
central, and participate in the catabolism of endogenous amines (noradrenaline).
Ultimately, the only enzyme catalyzing oxidative deamination of amino acids, whose distribution
in the organism and the activity are sufficient to explain the catabolism of amino acids, is the

glutamate dehydrogenase. This main pathway goes through a series of transformations between acids

amino acids and α-ketoglutaric acid, followed by oxidative deamination of the glutamic acid formed.
Glutamate dehydrogenase:

The enzyme is an NAD dehydrogenase + OR NADP + which catalyzes the reaction:

Glutamate + H 2O + NAD (P) + ¬¾® a -ketoglutarate + NAD(P)H,H+ + NH 3

The reaction is reversible and the reductive amination of α-ketoglutarate plays a role in the binding of

ammonia in the cells. It takes place in the mitochondria. Glutamate dehydrogenase (GDH) is

inhibited by GTP and ATP and activated by ADP and GDP in vitro. This therefore suggests that nucleotides regulate
the enzyme in vivo.

2- Other deamination methods:

• Deamination involving dehydration: this is the case of Serine which is metabolized by

serine dehydratase and therefore the coenzyme is PLP (pyridoxal phosphate). The enzyme is called

dehydratase because dehydration precedes deamination.

O
O O
H 2 oh   
      O-
HO OH HN O-   
      
O
NH 2 O

Ser α-iminopyruvic acid Pyr

Homework: Mechanism of action of PLP in deamination involving serine dehydration. A

analogous reaction is possible from threonine. Cysteine is deaminated by a mechanism

similar by a cysteine desulfhydrase. Briefly, the deamination of sulfur-containing L-amino acids and alcohol is
made in the presence of coenzyme PLP.

• Desaturating denaturation: involving the formation of a double bond. So Histidine is

deaminated to urocanate which then leads by opening of the imidazole nucleus to α-formimino L-
glutamate.

3- Decarboxylation:
In the presence of specific decarboxylases, amino acids can form carbon dioxide.

carbon and an amine according to the general reaction:

O
CO 2
   NH 3 +
R
OH
 
NH 2 R

The coenzyme is PLP. The importance of this transformation is quantitatively negligible, it has no

meaning only thanks to the properties of the amines formed.

Example: decarboxylation of Histidine leads to Histamine.

Decarboxylation of Tryptophan forms tryptamine which can be hydroxylated at 5 to give the

serotonin.

Intestinal bacteria have enzymes capable of decarboxylating Lysine and Ornithine.

respectively in cadaverine and putrescine, amines always present in small quantities in the intestine.
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But which can cause poisoning if their concentrations increase following fermentation

abnormal.
Certain PLP decarboxylases having amino acid substrates: Glu, DOPA, basic amino acids

or aromatics produce other amines encountered in metabolism.

  AA Amine Function
     
  Trp Serotonin  Neuromediator    

  Glu Amino butyrate

  Neuromediator    
  His Histamine  Neuromediator, immune mediator    
  Phe, Tyr Dopamine,
  norepinephrine, adrenaline Neurotransmitters,
  hormone  

  Asp ß-alanine  Component of coenzyme A    

  Cys Cysteamine
  Component of coenzyme A    

  Ser Ethanolamine
  Component of phospholipids    
  Thr Amino-propanol
  Component of vitamin B12    
       

4- Transamination:
Transamination reactions are characterized by the transport of an amino group. transamination or

aminotransfer is the general reaction of amino acid metabolism because it is involved both in
their catabolism than in their synthesis. It is the process that leads to an exchange of the α-amino group

between an α-amino acid and an α-keto acid. Enzymes that catalyze such reactions are called

aminotransferases or transaminases. Major aminotransferases exist in all tissues and

catalyzed reaction is reversible. The coenzyme involved is pyridoxal phosphate (group

prosthetics of all aminotransferases). It derives from vitamin B6. In the reactions of

transamination oriented towards the degradation of amino acids, the acceptor of the α-amino group is

always α-ketoglutarate. This results in the formation of glutamate.

Transaminases allow the entry of glucoforming amino acids into gluconeogenesis. All
these enzymes are regulated by cortisol, which induces their synthesis in cells that catabolize

proteins.

 
     
         

             

         
It should be noted that there is no net deamination, ie loss of the amino group in these reactions,

since the α-keto acid 2 is amino when the α-amino acid is deaminated.
The main purpose of this reaction is to collect the NH groups 2 of different amino acids under
form of a single product called Glutamate. The catabolism of amino groups therefore converges towards a

only product which is glutamate.

  
 

 
 

The Glutamate thus formed will undergo oxidative deamination to give ammonia or the ion

ammonium. This reaction regenerates the α-ketoglutarate needed in other transamination reactions.
The transamination reaction therefore has as its primary function the collection in the form of L-glutamate,

amino groups of different amino acids for elimination during oxidative deamination of

glutamate.

   

   
 

   

An important exception to the transaminases described above is a group of aminotransferases

muscles that accept Pyruvate as their α-ketoacid substrate. The amino acid (alanine) is released

in the blood and transported to the liver where it undergoes transamination to give Pyruvate which will be used in
gluconeogenesis. The resulting Glucose is returned to the muscles, where it is glycolytically broken down into

Pyruvate. This is the Glucose-Alanine cycle.

 
 
 
   

   
The amino group ends its journey either in ammonium or in aspartate for biosynthesis
urea. The Glucose-Alanine cycle therefore transports nitrogen from the muscle to the liver.
C)- UREA CYCLE.
Amino acids are the main source of ammonia formation in the body. Excess
of ammonia or ammonium ion must be removed. In humans, the ammonium ion is eliminated as

duration. The sequence of reactions that will take place includes a mitochondrial phase and a

cytosolic, all taking place only in the liver.

MITOCHONDRIAL PHASE
1-SYNTHESIS OF CARBAMOYL PHOSPHATE

In the mitochondria carbam(o)ylphosphate synthetase uses CO 2, the NH3 and 2ATP as substrates

to form carbam(o)ylphosphate. Two energy-rich phosphate bonds are consumed.

 
    
   
     
 
     
Carbamoyl-phosphate synthetase I, mitochondrial, involved in ureogenesis, is different from
carbamoyl-phosphate synthetase II, cytoplasmic which participates in the synthesis of pyrimidine nucleotides

(isoenzymes).

Carbamoyl-phosphate synthetase I, mitochondrial, involved in ureogenesis, must necessarily be

allosterically activated by N-acetyl glutamate, produced in the mitochondria by N-acetyl glutamate

synthetase. Carbamoyl-phosphate, in turn, is a glutaminase inhibitor.

2- SYNTHESIS OF CITRULLINE

It is done by interaction between carbamyl-P and ornithine with the help of the enzyme ornithine carbamyl

transferase.

 
 

  
   
 
 
Ornithine is an α-amino acid, a lower homolog of lysine, which does not participate in the synthesis of

proteins. Being an intermediary of several metabolic pathways, it is normally present in the matrix

mitochondria.

CYTOSOLIC PHASE
3-FORMATION OF ARGININOSUCCINATE.

The citrulline obtained in the 2th reaction is transferred to the cytosol. Under the action of argininosuccinate
synthetase, citrulline condenses with aspartate to give argininosuccinate with consumption of

two energy-rich phosphate bonds of an ATP molecule.

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4-FORMATION OF ARGININE
It is catalyzed by an argininosuccinate lyase which ensures the cleavage into L-arginine and fumarate. This
reaction is also involved in the synthesis of arginine.

 
   

    
 
 
 

 
Fumarate is transported into the mitochondria and taken up by the Krebs cycle which oxidizes it to oxaloacetate.

The latter will be transaminated into aspartate by aspartate aminotransferase. Thus is created a link between the

Krebs cycle and the Urea cycle.

5-HYDROLYSIS OF ARGININE

Arginine hydrolysis completes the cycle. It forms urea and ornithine. The reaction is catalyzed by
arginase.

  
   
    

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Arginase is an enzyme of the endoplasmic reticulum membrane of hepatocytes. It hydrolyses

arginine into ornithine and urea, then excretes the latter through the lumen of the reticulum cisternae outwards
of the cell. The ornithine released into the cytoplasm is again taken up by the mitochondria.

While urea is excreted for elimination through urine, ornithine is transported into the mitochondria
to restart the cycle.

The urea cycle reactions have been treated here individually. Duty urea cycle diagram.

CYCLE REPORT
The gross balance of the cycle is written:

                      
  

 
Pyrophosphatase hydrolyzes PPi to give 2Pi
During the formation of a urea molecule, 4 energy-rich bonds are used (2 ATP in 2

ADP+ 2 Pi and an ATP in AMP + PPi). When fumarate is transformed into oxaloacetate (Krebs cycle)
to regenerate the aspartate after transamination, this results in the formation of a molecule of NADH+H+ which

corresponds to 3 ATP. In conclusion, the elimination of a free ammonium ion and the amine from aspartate under
form of a urea molecule consumes only one energy-rich phosphate bond.

Regulation of the urea cycle:

Carbamoyl phosphate synthetase, the mitochondrial enzyme that catalyzes the key step in the urea cycle is

allosterically activated by N-acetyl glutamate. This metabolite is synthesized from Glutamate and
acetyl CoA by N-acetyl glutamate synthetase The production of urea by the liver is, in fact, correlated

by the concentration of N-acetyl glutamate. Increased urea synthesis is required when

amino acid degradation rates increase thereby generating excess nitrogen which should be
excreted. The increase in these speeds is signaled by an increase in the concentration of glutamate

through transamination reactions. This in turn causes an increase in the synthesis of N-acetyl

glutamate, stimulating carbamoyl phosphate synthetase and thereby all CU.

 
 
 
      
    
   
 
 
   
The other CU enzymes are controlled by the concentrations of their substrates.

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Inherited deficiencies of UC enzymes other than arginase do not lead to reductions

significant in urea production (complete absence of any of the UC enzymes leads to

death shortly after birth).

Ammonium ions produced by amino acid catabolism in all cells are taken up by
transamination on α-ketoglutarate, then by glutamine synthetase. The glutamine thus produced therefore carries

two nitrogen atoms. It diffuses into the circulation from where it is picked up by the kidneys or the liver.

D)-FUTURE OF THE CARBON SKELETON

After the departure of the α-amino group in the form of ammonia, the 20 amino acids, found in the

proteins, each release the corresponding α-ketoacid (carbon skeleton). The Degradation of 20 Skeletons
carbonaceous lead to the formation of seven compounds namely: α-ketoglutarate, oxaloacetate, fumarate,

acetoacetyl-CoA, succinyl-CoA, pyruvate and acetyl-CoA. They enter the intermediate metabolism to
the production of energy or for the synthesis of carbohydrates or lipids. Following the fate of the skeletons

carbonaceous, amino acids are classified into three groups:

-Glucoforming amino acids (glucogenic) ie precursors of glucose, including the degradation of

carbon skeleton release one of the following intermediates: α-ketoglutarate, oxaloacetate, fumarate,

succinyl-CoA and pyruvate. This class covers among the non-essential amino acids: alanine, asparagine,
aspartate, glutamate, glutamine, proline, glycine (glycol), serine, cysteine; and among the amino acids

essential: arginine, histidine, methionine, threonine and valine.

-Ketogenic (or ketonic) amino acids whose degradation of the carbon skeleton provides acetyl-
CoA or acetoacetyl-COA which are ketone bodies. Here we find 2 essential amino acids: leucine

and lysine.
-Amino acids that are both glucoforming and ketogenic: tyrosine (non-essential), phenylalanine,

tryptophan and isoleucine (all 3 essential).

E) BIOSYNTHESIS OF AMINO ACIDS

Nitrogen enters biosynthesis through amino acids and other biomolecules in reduced form.

Example: NH 3, NH 4+ . The assimilation of nitrogen therefore requires a reduction of these oxidized forms (N
2 and
NO 3-) in NH 4+. These processes take place in microorganisms and plants. The animals get

nitrogen from food.

The nitrogen cycle in the biosphere is entirely dependent on microorganisms, phenomena

main ones such as: atmospheric nitrogen fixation, nitrification, organic nitrogen ammonification,

are provided in part or in whole by bacteria, cyanophyceae and lower fungi.

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Nitrogen cycle in the biosphere
Living microorganisms have varying requirements for amino nitrogen, some bacteria are
+
capable of utilizing ammonium (NH 4 ) to synthesize amino acids and other nitrogenous molecules

organic; others, for example, higher plants use nitrate (NO -); on the other hand, the
3

Animals use nitrogen only in organic form.

Nitrogen fixation requires an enzyme complex called the nitrogenase complex. The conversion of
nitrogen to NH4+ by this complex requires ATP and a very strong reducing agent.

This nitrogenase complex contains two types of proteins: a reductase which supplies the electrons and a
+
nitrogenase which uses electrons to reduce nitrogen to NH 4 .
The fate of ammonium

Carbamoyl phosphate synthetase I, Glutamate dehydrogenase and Glutamine synthetase play

+
important roles in NH assimilation 4 .

Carbamoyl phosphate synthetase I uses two ATP molecules, one to activate bicarbonate, with
ammonium and the other to phosphorylate the carbamate formed.

Glutamate dehydrogenase which catalyzes the reductive amination of α-ketoglutarate to form the

glutamate.

               
Glutamine synthetase which catalyzes the ATP-dependent amidation of the γ-carboxyl of glutamate to
form glutamine.

             
The regulation of Gln synthetase plays an important role in nitrogen metabolism. GDH and GS are

present in all organisms. Most prokaryotes contain Glu synthetase which catalyzes
reductive amination of α-CG.

          
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When NH4+ is deficient, most Glu is produced by sequential action of Gln synthetase and Glu

synthetase.

                  
All non-essential amino acids except Tyr are synthesized from one of the four

common metabolic intermediates: Pyr, OA, α-CG, 3phospho glycerate. Tyrosine is synthesized at
from an essential amino acid Phe. Therefore the presence of Tyr in the diet decreases the

need for Phe.

All essential amino acids are synthesized from metabolic precursors. Their ways of
synthesis are present only in microorganisms and plants. Amino acids are

synthesized from the intermediates of the citric acid cycle, the intermediates of glycolysis and
pentose phosphate pathway. There are simply 6 biosynthetic families.

GLUTAMATE FAMILY
a-ketoglutarate leads to the glutamate family: glutamate, glutamine, proline, arginine

Glutamate and glutamine

During the assimilation of NH 3 we have seen that the synthesis of glutamate can take place thanks to the action:
- glutamate dehydrogenase according to the reaction:

            
- an aminotransferase (transaminase)

         
Regarding glutamine, it is synthesized under the action of glutamine synthetase.

       
Proline

It is formed from glutamate in two steps:

- The carboxylic function carried by carbon 5 is first reduced to an aldehyde.

It requires energy provided by ATP. It is catalyzed by glutamyl phosphate dehydrogenase.

               
- The previous semi-aldehyde glutamate undergoes cyclization followed by reduction to give proline.
Arginine
Arginine is an essential amino acid however it can be formed during ureogenesis
hepatic.

ASPARTATE FAMILY

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oxaloacetate leads to the aspartate family: aspartate, asparagine, methionine, threonine and isoleucine.

Aspartate

Aspartate is formed by transamination of oxaloacetate. The α-amino group is given by the

glutamate. The reaction is catalyzed by aspartate aminotransferase

         
Asparagine
Synthesis is catalyzed by asparagine synthetase

             
SERINE FAMILY

glycerate-3-phosphate leads to the serine family: serine, glycine, cysteine.

Serine

Serine is synthesized from 3-phosphoglycerate following the sequence below:

- Dehydrogenation leads to 3-phospho-hydroxypyruvate, catalyzed by 3-phosphoglycerate

dehydrogenase.
- It is followed by transamination in the presence of glutamate by a

phosphoserine transaminase.

PO-CH2-CO-COO + OOC-(CH) 2-CH-COO - - to PO-CH2-CH-COO

- - - + - OOC-(CH) -CO-COO
2
-

- Under the action of a phosphatase, serine is obtained by hydrolysis of the phosphate group

wisteria
Glycine is synthesized from serine by leaving the -CH2OH radical. The reaction is catalyzed by

serine hydroxymethyltransferase using tetrahydrofolate as a coenzyme.

Cysteine
Cysteine is formed from methionine by a sequence of complex reactions involving the

formation of S-adenosylmethionine, the only case where ATP is deprived of these 3 phosphate groups in
the same reaction:

The sequence below leads to cysteine (see degradation of methionine)

S-adenosylmethionine --------- to S-adenosylhomocysteine ---------- to Cysteine

   

ALANINE FAMILY
Pyruvate provides the alanine family: alanine, valine and leucine.

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Alanine

In this family, alanine represents the only non-essential amino acid. It is obtained by transamination
pyruvate in the presence of glutamate. The reaction is catalyzed by glutamate pyruvate aminotransferase

(GPAT or GPT=Glutamate Pyruvate Transaminase)

FAMILY OF AROMATIC AMINO ACIDS
Phosphoenolpyruvate and erythrose-4-phosphate are the starting point of phenylalanine, tyrosine and
tryptophan.
Tyrosine
This non-essential amino acid has the particularity of being derived from phenylalanine (amino acid

essential). It is considered as a degradation product of the latter. tyrosine or

parahydroxyphenylalanine is formed during a reaction catalyzed by phenylalanine hydroxylase.

The reducing power is provided by tetrahydrobiopterin (BH 4 ), oxygen comes from the air:

             
HISTIDINE FAMILY

Ribose-5-phosphate is the precursor to histidine.

Some amino acids, in addition to their main functions, are essential precursors of a variety
important molecules: nucleotides, nucleotide coenzymes, hemes, various hormones,

neurotransmitters and glutathione.

Homework: read about the biosynthesis and degradation of heme which is an essential prosthetic group of

several proteins including hemoglobin, myoglobin and cytochromes.

F) REGULATION OF PROTEIN METABOLISM

This regulation is on the one hand hormonal, on the other nutritional. This distinction is artificial since

in the majority of physiological circumstances, these two modes of regulation are simultaneous and act

in synergy during food intake.

1-Hormonal regulation

Hormones can be anabolic (promoting protein gain) or catabolic (promoting protein loss).

protein).
insulin

It is an anabolic hormone essential for protein gain and growth. Its mechanism
action in terms of synthesis and proteolysis, however, continues to be the subject of lively controversy. A

protein gain can indeed be obtained by increasing protein synthesis, by reducing the

proteolysis or by both phenomena combined.

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At the cellular and molecular level, insulin increases protein synthesis by stimulating transcription and

the translation. At the tissue level, insulin stimulates muscle protein synthesis, particularly in
young growing animal or when used at a pharmacological dose or when insulin is

added from a completely insulin-deprived situation. In adults, and especially in humans,

insulin is essentially anabolic through a reduction in proteolysis, whether in the body

whole or muscle. In this situation, insulin does not seem to have any effect on protein synthesis.

growth hormone
It is essentially anabolic through a stimulating effect on protein synthesis acting directly and

through growth factors (IGF1). This property could be exploited in humans

to prevent muscle wasting in the elderly (and illegally in sports circles to increase

muscle mass).
Catecholamines

Contrary to popular belief, it has now been clearly demonstrated that catecholamines are not
no catabolic hormones vis-à-vis protein metabolism. According to the authors, they reduce the

proteolysis or increase protein synthesis.

Glucorticoids
They are catabolic by increasing muscle proteolysis and by inhibiting the translation of

proteins as evidenced by the protein melting observed during hypercorticism (disease of

Cushing) or long-term glucocorticoid therapy.

Thyroid hormones and glucagon

They have more complex effects:

• with regard to thyroid hormones, hyperthyroidism induces muscle wasting suggesting a

increase in proteolysis and also a reduction in protein synthesis in different tissues.

However, these phenomena and in particular the reduction of protein synthesis are also found
in situations of hypothyroidism and it is also known that thyroid hormones are

essential for growth. It is therefore difficult to classify thyroid hormones as

anabolic or catabolic and an average optimal level of thyroid hormone can be said to be
necessary for a good balance between synthesis and degradation.

As for glucagon, its actual importance in regulating protein metabolism is disputed.

and seems to be mainly at the level of the splanchnic metabolism of amino acids. Despite data

contradictory, a catabolic effect seems predominant.

Cytokines (TNF, interleukins)

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They are catabolic at the muscle level. Their effects vary according to cytokines and tissues. The
cytokines like TNF act in synergy with cortisol and the combination of their effects causes a

rapid and massive proteolysis causing muscle protein wasting.

2-Nutritional regulation

It will be considered from two aspects:

-First regulation by the substrates themselves, whether amino acids or other substrates
energy,

a) amino acids: whether in vitro or in vivo, amino acids globally stimulate the synthesis
protein.

b) other energy substrates: in general, a sufficient energy supply is essential to the

maintaining a neutral or positive nitrogen balance. The source of energy intake is not indifferent and
classically, carbohydrates would have a nitrogen-sparing effect greater than that of lipids, at least in

circumstances of limited energy intake. This notion is much debated or even erroneous for some and
anyway, is no longer true when the energy intake is in excess.

-Then, the evolution of protein metabolism during the different nutritional circumstances that

are eating and fasting.

Three successive states are defined in the physiology of nutrition:

-The nourished state corresponds to the period during which ingested nutrients arrive from the digestive tract in

the circulation.
-The post-absorptive state corresponds to the 12 to 18 hours following the nourished state, that is to say in the morning on an empty stomach.

-The state of fasting, which can be either short (2 to 3 days) or prolonged (greater than 3 days).
a) In the post-absorptive state, synthesis, proteolysis and oxidation are at their basal level, proteolysis

being slightly higher than the synthesis and the organism being in negative balance. This basal level of
protein renewal depends on the protein intake of the previous days, it is accelerated in the event of intake

important, reduced in case of weak contributions. At the tissue level, in this circumstance, the muscle is a
net producer of amino acids in moderate quantity.

b) During a meal (nourished state): by mechanisms linked both to the supply of substrates and to

hyperinsulinemia, the body is then in positive balance. The oxidation of amino acids in muscle
(for branched amino acids) and especially in the liver, increases massively which corresponds to a

high urinary nitrogen. This increase is proportional to the protein intake and corresponds for

the body to a means of eliminating the excess amino acids, the desired goal being to obtain at the
end of a nychthemeron (nourished state + post absorptive state) with zero nitrogen balance.

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c) The body then returns to the post absorptive state then to the short fast: Multiple modifications

metabolic hormones will occur. During the short fast, the initial nitrogen balance is strongly negative

with significant losses of nitrogen. At this phase, proteolysis is high, the muscle supplying acids
 amino acids for gluconeogenesis and protein synthesis slowly decreases.
d) During long fasting: nitrogen excretion will decrease to stabilize around 50 mg/kg/day,

which constitutes the obligatory nitrogen losses. Of course, proteolysis remains superior to synthesis (hence the
negative balance) but, overall, protein renewal tends to decrease with proteolysis values

which are rapidly lower than they are in the post absorptive state. This relative nitrogen saving,
minimizing the reduction in protein mass, is an essential defense mechanism during

fasting in humans and mammals.

GENETIC DISEASES OF AMINO ACID METABOLISM.

Genetic diseases of amino acid metabolism include diseases related to

anomaly in the metabolism of amino acids due to a defect in the enzymatic functioning of one of the enzymes.

  Name Transmission Enzyme

     

  Phenylketonuria Recessive Phenylalanine

  hydroxylase    

  Tyrosinemia Type 1 Recessive Fumaryl  aceto-acetase    

  Tyrosinemia Type 2 Recessive Tyrosine  transaminase    

  Tyrosinemia Type 3 Recessive 4-hydroxyphenylpyruvate

   dioxygenase  

  Alkaptonuria Recessive Homogentisate  1,2-dioxygenase    

  Recessive Homocystinuria Cystathionine

  beta-synthase    

  Histidinemia Recessive Histidase      

  Leucinosis Maple syrup disease Recessive

  Keto-acid decarboxylase
   

  Methylmalonic aciduria Recessive Methylmalonyl-coenzyme

    A mutase  

  Hyperglycinemia without ketosis Recessive

  Glycine synthase
   

  Recessive Hyperlysinemia Glycine alpha-ketoglutarate

  reductase
   

  Phenylketonuria:      

In phenylketonurics, the transformation of phenylalanine cannot occur and phenylalanine

then accumulates in the blood as the tyrosine level is lowered. Excess phenylalanine in the blood

is toxic to the nervous system, and disrupts brain development in children, resulting in
Mental retardation. Lower tyrosine levels lead to lower melanin production, which

which causes affected children to tend to have pale hair, complexion and eyes (tends

whitish).
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Tyrosinemia

Tyrosinemia is an inherited metabolic disease that renders the body unable to assimilate
tyrosin. There are three types of tyrosinemia based on deficient enzymes.

We have tyrosinemia type I, II and III represented as follows.

 
  

 
  

 
  

Type III is the rarest.

Explanation: a deficiency of one of these enzymes leads to the accumulation of intermediate metabolites such as

tyrosine which can have more or less serious consequences.

Homocystinuria

Homocysteine is an amino acid resulting from the metabolism of methionine, and which is itself

transformed into cysteine. Homocystinuria is an inherited metabolic disorder that prevents

transformation of homocysteine into cysteine. It is therefore characterized by the accumulation

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homocysteine in blood and urine. It can cause mental retardation, problems with

vision and a significant cardiovascular risk.

Leucinosis

Leucinosis (or MSUD, Maple Syrup Urine Disease) is an inherited metabolic disorder in
which the body is unable to metabolize branched chain amino acids (leucine, isoleucine and

worthy). Normally, these amino acids are broken down by the multi-enzyme complex

ketodecarboxylase. The lack of enzyme causes the accumulation of leucine, isoleucine and valine in the
blood resulting in acidosis which can be severe during the first week of life.

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