Non-standard Amino Acids

Introduction: Amino acids are the building blocks of protein. They represent the source of life and make up 20 percent of the human body.

Amino acids are the oldest nutrients that have existed on earth. They have been used as the source of life over the period from primordial life to the present stage of evolution marked by the appearance of man. About half of the remaining part consists of amino acids (including proteins). Amino acids perform various important functions for the body and serve as the materials for the body's cells, hormones, and enzymes.
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Amino Acids are the chemical units or "building blocks" of the body that make up proteins. Protein substances make up the muscles, tendons, organs, glands, nails, and hair. Growth, repair and maintenance of all cells are dependent upon them. Next to water, protein makes up the greatest portion of our body weight.
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Amino Acid: The molecules consisting of the basic amino group (NH2), the acidic carboxylic group (COOH), a hydrogen atom (-H), and an organic side group (R) attached to the carbon atom, thus, having the basic formula of NH2CHRCOOH, are called amino acids. Amino acids are the building block of protein in which each is coded for by a codon and linked together through peptide bonds. [3]

They are particularly important in biomolecular pharmacy, where the term usually refers to alpha-amino acids.

A peptide bond (amide bond) is a covalent chemical bond formed between two molecules when the carboxyl group of one molecule reacts with the amino group of the other molecule, thereby releasing a molecule of water

Non-standard Amino Acids

Classification of Amino Acid: According to Nelson D. L. & Cox M. M. (2004), Lehninger Principal of Biochemistry, 3rd ed. Amino acids can be divided as; 1. Standard amino acids 2. Non-standard amino acids

1. Standard amino Acids: Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino acids. Of these, 20 are encoded by the universal genetic code. [4] All these 20 amino acids are found in proteins & are -amino acids. The 20- amino acids of proteins are often referred as Standard Amino Acids. [5]

2. Non Standard Amino Acids: There are many other amino acids that are called non-proteinogenic or non-standard. Nonstandard amino acids refer to those amino acids that have been chemically modified after they have been incorporated into a protein and those amino acids that occur in living organisms but are not found in proteins. [6]

Those either are not found in proteins (for example carnitine, GABA), or are not produced directly and in isolation by standard cellular machinery (for example, hydroxyproline and selenomethionine). [7]

Non-standard amino acids that are found in proteins are formed by post-translational modification, which is modification after translation during protein synthesis.

Post-translational modification (PTM) is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis for many proteins.

Non-standard Amino Acids

Types of Nonstandard amino acids: According to Nelson D. L. & Cox M. M. (2004), Lehninger Principal of Biochemistry, 3rd ed. Amino acids can be of tow types; a. Nonstandard amino acids found in proteins b. Nonstandard amino acids which are not found in proteins

a. Nonstandard Amino Acids Found in Proteins Some non standard amino acids are found in proteins. All are derived from standard amino acids by post-translational modification. These include; o 4-hydroxyproline o 5-hydroxylysine o 6-N-Methyllysine o -Carboxyglutamate o Desmosine o Selenocysteine

4-Hydroxyproline 4-Hydroxyproline or L-hydroxyproline is a common non-proteinogenic amino acid, and is a derivative of proline. Molecular Formula: C5H9O3N Structure:

Production: Hydroxyproline is produced by hydroxylation of the amino acid proline by the enzyme prolylhydroxylase following protein synthesis (as a post-translational modification). The enzyme catalyzed reaction takes place in the lumen of the endoplasmic reticulum. [8]
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Non-standard Amino Acids

Importance:

Hydroxyproline and proline play key roles for collagen stability. They permit the sharp twisting of the collagen helix.[10]

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Hydroxylation of proline has been shown to be involved in targeting Hypoxiainducible factor (HIF) alpha subunit (HIF-1 alpha) for degradation by proteolysis.[11]

Hydroxyproline is found in few proteins other than collagen. The only other mammalian protein that includes hydroxyproline is elastin.[12]

Increased serum and urine levels of hydroxyproline have also been demonstrated in Paget's disease.[14]

5-Hydroxylysine 5-Hydroxylysine is a hydroxy derivative of lysine. It was first discovered in 1921 by Donald Van Slyke. It is a hydroxy derivative of lysine. It is most widely known as a component of collagen. [15] Molecular Formula: C6H14N2O3 Structure:

Production: It is biosynthesized from lysine via oxidation by the enzyme lysyl hydroxylase. Importance: The decreased ability to form 5-hydroxylysine is associated with Ehlers-Danlos syndrome type VI. [15]

EhlersDanlos syndrome (EDS) (also known as "Cutis hyperelastica) is a group of inherited connective tissue disorders, caused by a defect in the synthesis of collagen (a protein in connective tissue - usually Type I and III).

Non-standard Amino Acids

6-N-Methyllysine 6-N-Methyllysine is a constituent of myosin, a contractile protein of muscle. [5] Molecular Formula: C7H16N2O3 Structure:

Importance: Methyllysine plays an important role in epigenetics. [16] the methylation of specific lysines of certain histones in a nucleosome alters the binding of the surrounding DNA to those histones, which in turn affects the expression of genes on that DNA.[16] -Carboxyglutamate The amino acid gamma-carboxyglutamate is the product of post-translational vitamin Kdependent carboxylation of peptide bound glutamic acid residues. [17] Molecular Formula: C6H7O6N Structure:

Importance: It is found in the blood clotting protein prothombin and in certain other protein that bind Ca2+ as part of their biological function. Gamma-carboxyglutamate in a neuroactive toxin. [17]

Non-standard Amino Acids

Desmosine Demosine is a derivative of four Lys residues, which is found in fibrous protein elastin.[5] Molecular Formula: C24H40N5O8 Structure:

Importance: Desmosine causes a yellow color. [18] This desmosine is responsible for the rubber properties of elastin. [18]

Selenocysteine Selenocysteine is a special case. This rare amino acid residue introduced during protein synthesisrather than created through a postsynthetic modification. It contains selenium rather than the sulfur of cysteine. It actually derived from serine; selenocysteine is constituent of just a few proteins. [5] Molecular Formula: C3H7NO2Se Structure:

Importance: Selenocysteine has both a lower pKa and a higher reduction potential than cysteine. These properties make it very suitable in proteins that are involved in anti-oxidant activity. [19] Its high reactivity would incur damage to cells. [19] Selenocysteine synthesis occurs on a specialized tRNA, which also functions to incorporate it into nascent polypeptides.[19]
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Non-standard Amino Acids

b. Nonstandard amino acids which are not found in proteins: Some 300 nonstandard amino acids are have been found in cells. They have a variety of function but are not found in proteins. Ornithine and citrullin deserve the special note because the are key intermediates in the biosynthesis of arginine and in urea cycle. [5]

Ornithine L-Ornithine is one of the products of the action of the enzyme arginase on L-arginine, creating urea. Ornithine is not an amino acid coded for by DNA, and, in that sense, is not involved in protein synthesis.[20] Molecular Formula: C5H12N2O2 Structure:

Importance: ornithine is a central part of the urea cycle, which allows for the disposal of excess nitrogen. Ornithine is also the starting point for cocaine biosynthesis, when

decarboxylased, then modified greatly by Cytochrome P450.

Citrullin The organic compound citrulline is an -amino acid. Its name is derived from citrullus, the Latin word for watermelon, from which it was first isolated in 1930.[21] Molecular Formula: C6H13N3O3 Structure:

Non-standard Amino Acids

Biosynthesis: Citrulline is made from ornithine and carbamoyl phosphate in one of the central reactions in the urea cycle. It is also produced from arginine as a by-product of the reaction catalyzed by NOS family. Arginine is first oxidized into N-hydroxyl-arginine, which is then further oxidized to citrulline concomitant with release of nitric oxide. [22] Importance: It is a key intermediate in the urea cycle, the pathway by which mammals excrete ammonia. [22] Proteins that normally contain citrulline residues include myelin basic protein (MBP), filaggrin, and several histone proteins, whereas other proteins, such as fibrin and vimentin are susceptible to citrullination during cell death and tissue inflammation. [22] Patients with rheumatoid arthritis often have detectable antibodies against proteins containing citrulline. [22] Although the origin of this immune response is not known, detection of antibodies reactive with citrulline (anti-citrullinated protein antibodies) containing proteins or peptides is now becoming an important help in the diagnosis of rheumatoid arthritis. [22] In recent studies, citrulline has been found to relax blood vessels. [22] Citrulline in the form of citrulline malate is sold as a performance-enhancing athletic dietary supplement, which was shown to reduce muscle fatigue in a preliminary clinical trial. [22]

Other Nonstandard amino acids which are not found in proteins: o Gamma-aminobutyric acid o Carnitine o Lanthionine o Dehydroalanine

Non-standard Amino Acids

Gamma-aminobutyric acid chemically it is an amino acid, GABA is rarely referred to as such in the scientific or medical communities, because the term "amino acid," used without a qualifier, conventionally refers to the alpha amino acids, which GABA is not, nor is it a protein.[23] Molecular Formula: C4H9NO2 Structure:

Synthesis GABA does not penetrate the blood-brain barrier; it is synthesized in the brain. It is synthesized from glutamate using the enzyme L-glutamic acid decarboxylase and pyridoxal phosphate (which is the active form of vitamin B6) as a cofactor via a metabolic pathway called the GABA shunt. This process converts glutamate, the principal excitatory neurotransmitter, into the principal inhibitory neurotransmitter (GABA) [23] Importance: It is the chief inhibitory neurotransmitter in the mammalian central nervous system. [23] It plays a role in regulating neuronal excitability throughout the nervous system.
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In humans, GABA is also directly responsible for the regulation of muscle tone.
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Drugs that act as agonists of GABA receptors1 (known as GABA analogues or GABAergic drugs) or increase the available amount of GABA typically have relaxing, anti-anxiety, and anti-convulsive effects. [25]

GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. [26]

The GABA receptors are a class of receptors that respond to the neurotransmitter gammaaminobutyric acid (GABA), the chief inhibitory neurotransmitter in the vertebrate central nervous system.

Non-standard Amino Acids

Carnitine Carnitine is a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine. [27] Molecular Formula: C7H15NO3 Structure:

Importance: In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (fats) for the generation of metabolic energy. [28] It is often sold as a nutritional supplement. Carnitine was originally found as a growth factor for mealworms and labeled vitamin Bt. Carnitine exists in two stereoisomers: Its biologically active form is L-carnitine, whereas its enantiomer, D-carnitine, is biologically inactive. [28] The carnitines exert a substantial antioxidant action, thereby providing a protective effect against lipid peroxidation of phospholipid membranes and against oxidative stress induced at the myocardial and endothelial cell level. [29] Because kidneys produce carnitine, kidney disease may lead to the deficiency of carnitine in the body. Thus, carnitine may be prescribed to those with kidney disease. [30] Regular supplements of L-carnitine, however, contribute to energy metabolism and improved neurotransmitter function in the brain in elderly patients. [28]

Nutritional supplement, is a preparation intended to supplement the diet and provide nutrients, such as vitamins, minerals, fiber, fatty acids, or amino acids, that may be missing or may not be consumed in sufficient quantities in a person's diet.

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Non-standard Amino Acids

Lanthionine Lanthionine is a nonproteinogenic amino acid. As the monosulfide analog of cystine, lanthionine is composed of two alanine residues that are crosslinked on their -carbon atoms by a thioether linkage. Despite its name, lanthionine does not contain lanthanum.[31] Molecular Formula: C6H12N2O4S Structure:

Dehydroalanine Dehydroalanine is an uncommon amino acid found in peptides of microbial origin (an unsaturated amino acid). Molecular Formula: C3H5NO2 Structure:

Importance: Many dehydroalanine-containing peptides are toxic or antibiotic and constitute parts of lantibiotics or microcystins.

Conclusion: The non-standard amino acids have the importance that the standard amino acids have. They are also used as drugs and nutritional supplements. So the study of the nonstandard amino acids, their sources, structures, molecular formula and functions deserve a great importance in the study of biomolecular pharmacy.
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