When Tyrosine becomes an essential amino acid

Answer to Question AM-06

 

Short answer: (g)

 

In patients with PKU, Tyrosine becomes essential, since it is formed from Phenylalanine in the reaction that is impaired in Phenylketonuria.

 

Additional information:

 

Most of the textbooks classify amino acids from the nutritional point of view, in two groups: essential or not essential.  Essential amino acids are considered those amino acids that can not be synthesized by an organism and so should be consumed in the diet; non essential amino acids are those amino acids that can be synthesized.  This classification is not related to the importance of the amino acids, but with the fact of them being required in the diet or not.

 

According to this classification, the essential amino acids are:

 

Arginine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Threonine, Tryptophan, Valine

 

(Mnemonics:

PriVaTe TIM HALL:

 

Phenylalanine

Valine

Threonine

 

Tryptophan

Isoleucine

Methionine

 

Histidine

Arginine

Leucine

Lysine)

 

Non essential amino acids are:

Alanine, Asparagine, Aspartate, Cysteine, Glutamate, Glutamine, Glycine, Proline, Serine, Tyrosine

 

Like most facts in biology, this “black and white” classification is not 100 % accurate. Actually, some amino acids are conditionally essential or partially essential, since some “essential” amino acids, like arginine,  can be synthesized by the body. Arginine is synthesized in the urea cycle, for example, but it is considered essential since the quantity of Arginine that is synthesized is not enough during the growing process.

 

 Tyrosine is an amino acid that is synthesized in the body from Phenylalanine, that is an essential amino acid. This reaction is catalyzed by the enzyme Phenylalanine Hydroxylase, that use as cofactor reduced tetrahydobiopterine.

If Phenylalanine is deficient in the diet, then the body requires tyrosine in the diet.

 

In Phenylketonuria there is an excess of Phenylalanine, since the body can not metabolize it, but Phenylketonuria is a consequence of a deficit of Phenylalanine Hydroxylase (Classic Phenylketonuria) or a deficit of Tetrahydrobiopterin Reductase. In both cases, the organism is not able to synthesize Tyrosine from Phenylalanine, so even when there is an accumulation of Phe in these patients, it can not be used to synthesize Tyrosine.

 

In fact, some of the signs and symptoms of Phenylketonuria, like mental retardation and other neurological symptoms, have been related to the unavailability of tyrosine for the synthesis of the neurotransmitters that derive from tyrosine.

 

 

The lack of pigmentation of PKU patients, has been related also to the lack of tyrosine, since Tyrosine is a precursor of melanine also.

 

It is obvious that if Tyrosine is formed in normal persons from phenylalanine through the reaction cited above, in case that this reaction can not be produced, like in PKU, it is necessary to supplement the patient with Tyrosine, since the patient can not synthesize it, so Tyrosine becomes an essential amino acid for these patients.

 

 

About Arginine

Answer to Biochemistry Question AM-05

 

(b) Arginine

 

Structure of arginine

 

                                                 

 

 

                                                                        

  

Arginine is for humans a conditional essential amino acid, since we can synthesize, but it may not be enough for our requirements, depending of the health status and the stage of development. For infants, arginine is nutritionally essential, and in adults some must still be consumed through diet, especially in some conditions as trauma, burn injury, small-bowel resection and renal failure.

 

Arginine is synthesized from citrulline. Citrulline is formed mainly in the small intestine and is recovered from circulation by the kidney, that converts most of it in arginine (it explains the increased requirement of arginine in patients with renal failure of small-bowel resection).

 

 Not only the kidney and the liver, where Urea Cycle occurs, can produce arginine. In fact, several tissues can synthesize, in lower quantities, this amino acid, since it can yield important biologically active compounds.

 

As mentioned before, an important source of arginine is the diet. Arginine is found in a variety of foods including meats, dairy products and seafood. It appears also in vegetarian food as wheat germ, nuts, seeds, soybeans and others. Some energy drinks and body builder supplements are enriched with arginine.

 

Arginine, as stated in the question, is the precursor of Nitric Oxide and Urea.

 

 

The synthesis of Nitric Oxide occurs in a two steps reaction catalyzed by Nitric Oxide Synthase (NOS) that produces NwHydroxy-L Arginine (NOHLA) as an intermediary:

 

L-Arg + NADPH.H+ + O2  à [Nw-hydroxy-Larginine] + NADP+ +H2O

[Nw-hydroxy-Larginine] + NADPH.H+ + O2  à citrulline  + NO + NADP+

 

 

Nitric oxide synthase contains as cofactors FMN, FAD, tetrahydrobiopterin and Fe⁺⁺⁺ Hem. There are three isoforms of this enzyme and it is present in many tissues and cell types: neurons, macrophages, hepatocytes, myocytes of smooth muscle, endothelial cells of the blood vessels and epithelial cells of the kidneys.

 

 

The synthesis of urea from arginine occurs in the last reaction of the Urea Cycle:

 

L-Arg + H2O —-à ornithine + Urea

 

This reaction is catalyzed by Arginase, an enzyme with two isoforms: Arginase I, expressed in the cytoplasm of the liver, and related to Urea Cycle, and Arginase II, that appears in several tissues and apparently act, as a competing enzyme for the same substrate, like some kind of regulator of the arginine available for the action of Nitric Oxide Synthase.

 

Besides the importance of Arginine as a precursor of Nitric Oxide and Urea, and its obvious role as one of the 20 amino acids that constitute the “building blocks” of proteins, Arginine is also precursor of Creatine, and can be interconverted with other amino acids as proline and glutamate. Arginine also can yield other nitrogenated compounds, depending on the specific tissue.

 

As described by Morris, (one of the authors that has focused on Arginine research during the last years): “L-arginine is catabolized by arginases, nitric oxide synthases, arginine: glycine amidinotransferase, and possibly also by arginine decarboxylase, resulting ultimately in the production of urea, proline, glutamate, polyamines, nitric oxide, creatine, or agmatine. There is considerable diversity in tissue-specific and stimulus-dependent regulation of expression within this group of enzymes, and the expression of several of them can be regulated at transcriptional and translational levels by changes in the concentration of L-arginine itself.” (Morris, S.M. Jr: Enzymes of Arginine Metabolism  (J Nutr.134 (10 Suppl):2743S-2747S; discussion 2765S-2767S, 2004) 

 

 

 More information about Arginine and Arginine metabolism in:

  

Morris, S.M. JR.: Arginine, Beyond Protein, Amer J Clin Nutr 83(2)  508S-512S, 2006

 

 

Morris, S.M. Jr. Arginine metabolism: boundaries of our knowledge (J Nutr 2007) 137(6 Suppl 2):1602S-1609S.

 

King, The Medical Biochemistry Page: amino acid derivatives

 

Nitric Oxide Synthase

 

Good graphics about Urea synthesis in:

 

http://www.wiley.com/college/fob/quiz/quiz20/20-8.html

 

 Arginine (Wikipedia)

 

 For the uses of Arginine based on scientific evidence:

 

 

MedlinePlus Herbs and Supplements: Arginine (L-arginine)

 

 

Ammonia Detoxification: From Muscle to Liver

 

Answer to Biochemistry Question AM-04

 

Answer:  (a) alanine and glutamine

 

 

 

 

                                                  

 

At cellular pH NH3 exists as NH4⁺ ion. If the concentration of ammonium ions is very high, coma may result ( “Hepatic coma”).

 

There are mechanisms in our body to avoid hyperammonemia. Those mechanisms allow the transport of ammonia from muscle and other peripheral tissues to the liver and the kidneys.

 

 

 

 

                                                             

 

 In the liver, the ammonia delivered by these mechanisms will form UREA, while in the kidneys these mechanism will allow the direct excretion of NH4⁺  in urine.

 

These mechanisms are:

 

- Glucose-alanine cycle (transport of  NH3 from muscle to liver).

 

- Glutamine synthase/glutaminase system (transport of NH3 from different tissues to kidney and liver)

 

  Ammonia Detoxification in Muscle:

 

 Alanine transaminase has an important function in the delivery of skeletal muscle carbon and nitrogen (in the form of alanine) to the liver. In the glucose-alanine cycle ammonium ion is transported from muscle cells to the liver in the form of alanine.

 

Through glycolysis, glucose becomes pyruvate in the muscle. The participation of this ketoacid (pyruvate) in transamination reactions produce the corresponding amino acid: alanine. Alanine is then transported to the liver, where it can be transaminated again producing pyruvate that can be used for gluconeogenesis yielding glucose that can be send again to the muscle for producing energy (glucose-alanine cycle).

 

The other mechanism for transporting nitrogen in a non toxic form from the muscle to the liver is in form of glutamine. The enzyme glutamine synthase (also present in the liver) catalyses the following reaction:

 

Glutamate + NH3 + ATP ———-à glutamine +ADP + (P)

 

This reaction allows the transportation of nitrogen in a non toxic form to the liver and kidney (this reaction is important for other things, also!). Glutamine is the major amino acid found in the circulatory system, followed by alanine. The role of glutamine in the blood is to carry ammonia to and from various tissues but principally from peripheral tissues like the muscle, to the kidney and liver, where the amide nitrogen is hydrolyzed by the enzyme glutaminase and the ammonia is released, forming H4+ ion. In the kidney, it can be excreted in the urine by direct renal excretion, while in the liver the ammonia released by glutaminase will be used mainly for the synthesis of urea.

 

Note that ammonia arising in muscle and other peripheral tissues is carried in a nonionizable form as alanine or glutamine from to the liver. In these forms, ammonia does not have the toxic properties of free ammonia.

 

 More information ca be found in:

 

Brosnan, J.T.: Interorgan Amino Acid Transport and its Regulation

 

 The medical biochemical page: Nitrogen metabolism

 

 Vey good graphics about the glucose-alanine cycle, can be found in this link.