Amino acid synthesis

Amino acid synthesis

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For the non-biological synthesis of amino acids see: Strecker amino acid synthesis
Strecker amino acid synthesis
The Strecker amino acid synthesis, devised by Adolph Strecker, is a series of chemical reactions that synthesize an amino acid from an aldehyde . The aldehyde is condensed with ammonium chloride in the presence of potassium cyanide to form an α-aminonitrile, which is subsequently hydrolyzed to give...



Amino acid synthesis is the set of biochemical processes (metabolic pathways) by which the various amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

s are produced from other compounds
Chemical compound
A chemical compound is a pure chemical substance consisting of two or more different chemical elements that can be separated into simpler substances by chemical reactions. Chemical compounds have a unique and defined chemical structure; they consist of a fixed ratio of atoms that are held together...

. The substrates for these processes are various compounds in the organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...

's diet or growth media. Not all organisms are able to synthesise all amino acids. For example, humans are able to synthesise only 12 of the 20 standard amino acids.

A fundamental problem for biological systems is to obtain nitrogen
Nitrogen
Nitrogen is a chemical element that has the symbol N, atomic number of 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless, and mostly inert diatomic gas at standard conditions, constituting 78.08% by volume of Earth's atmosphere...

 in an easily usable form. This problem is solved by certain microorganisms capable of reducing the inert N≡N molecule (nitrogen gas) to two molecules of ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...

 in one of the most remarkable reactions in biochemistry. Ammonia is the source of nitrogen for all the amino acids. The carbon backbones come from the glycolytic pathway, the pentose phosphate pathway
Pentose phosphate pathway
The pentose phosphate pathway is a process that generates NADPH and pentoses . There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars...

, or the citric acid cycle
Citric acid cycle
The citric acid cycle — also known as the tricarboxylic acid cycle , the Krebs cycle, or the Szent-Györgyi-Krebs cycle — is a series of chemical reactions which is used by all aerobic living organisms to generate energy through the oxidization of acetate derived from carbohydrates, fats and...

.

In amino acid production, one encounters an important problem in biosynthesis, namely stereochemical control. Because all amino acids except glycine are chiral, biosynthetic pathways must generate the correct isomer with high fidelity. In each of the 19 pathways for the generation of chiral amino acids, the stereochemistry at the α-carbon atom is established by a transamination
Transamination
There are two chemical reactions known as transamination . The first is the reaction between an amino acid and an alpha-keto acid...

 reaction that involves pyridoxal phosphate. Almost all the transaminases that catalyze these reactions descend from a common ancestor, illustrating once again that effective solutions to biochemical problems are retained throughout evolution.

Biosynthetic pathways are often highly regulated such that building-blocks are synthesized only when supplies are low. Very often, a high concentration of the final product of a pathway inhibits the activity of enzymes that function early in the pathway. Often present are allosteric enzymes capable of sensing and responding to concentrations of regulatory species. These enzymes are similar in functional properties to aspartate transcarbamoylase and its regulators. Feedback and allosteric mechanisms ensure that all twenty amino acids are maintained in sufficient amounts for protein synthesis and other processes.

Amino acid synthesis


Amino acids are synthesized from α-ketoacids, and later transaminated from another aminoacid, usually Glutamate. The enzyme involved in this reaction is an aminotransferase.
α-ketoacid + glutamate ⇄ amino acid + α-ketoglutarate


Glutamate itself is formed by amination
Amination
Amination is the process by which an amine group is introduced into an organic molecule. Enzymes which catalyse this reaction, are termed aminases. This can occur in a number of ways including reaction with ammonia or another amine such as an alkylation, reductive amination and the Mannich reaction...

 of α-ketoglutarate:
α-ketoglutarate + ⇄ glutamate

Nitrogen fixation: Microorganisms use ATP and a powerful reductant to reduce atmospheric nitrogen to ammonia


Microorganisms use ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

 and reduced ferredoxin
Ferredoxin
Ferredoxins are iron-sulfur proteins that mediate electron transfer in a range of metabolic reactions. The term "ferredoxin" was coined by D.C. Wharton of the DuPont Co...

, a powerful reductant, to reduce N2 to NH3. An iron-molybdenum cluster in nitrogenase deftly catalyzes the fixation of N2, a very inert molecule. Higher organisms consume the fixed nitrogen to synthesize amino acids, nucleotides, and other nitrogen-containing biomolecules. The major points of entry of NH4+ into metabolism are glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...

 or glutamate.

Amino acids are made from intermediates of the citric acid cycle and other major pathways


Of the basic set of 20 amino acids (not counting selenocysteine
Selenocysteine
Selenocysteine is an amino acid that is present in several enzymes .-Nomenclature:...

), there are 8 that human beings cannot synthesize. In addition, the amino acids arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

, cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

, glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

, glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...

, histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

, proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

, serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

, and tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 are considered conditionally essential, meaning they are not normally required in the diet, but must be supplied exogenously to specific populations that do not synthesize it in adequate amounts. For example, enough arginine is synthesized by the urea cycle to meet the needs of an adult but perhaps not those of a growing child. Amino acids that must be obtained from the diet are called essential amino acids. Nonessential amino acids are produced in the body. The pathways for the synthesis of nonessential amino acids are quite simple. Glutamate dehydrogenase catalyzes the reductive amination of α-ketoglutarate to glutamate. A transamination reaction takes place in the synthesis of most amino acids. At this step, the chirality of the amino acid is established. Alanine
Alanine
Alanine is an α-amino acid with the chemical formula CH3CHCOOH. The L-isomer is one of the 20 amino acids encoded by the genetic code. Its codons are GCU, GCC, GCA, and GCG. It is classified as a nonpolar amino acid...

 and aspartate are synthesized by the transamination of pyruvate and oxaloacetate, respectively. Glutamine is synthesized from NH4+ and glutamate, and asparagine
Asparagine
Asparagine is one of the 20 most common natural amino acids on Earth. It has carboxamide as the side-chain's functional group. It is not an essential amino acid...

 is synthesized similarly. Proline
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...

 and arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...

 are derived from glutamate. Serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...

, formed from 3-phosphoglycerate, is the precursor of glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

 and cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

. Tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...

 is synthesized by the hydroxylation of phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...

, an essential amino acid. The pathways for the biosynthesis of essential amino acids are much more complex than those for the nonessential ones.

Tetrahydrofolate, a carrier of activated one-carbon units, plays an important role in the metabolism of amino acids and nucleotides. This coenzyme carries one-carbon units at three oxidation states, which are interconvertible: most reduced—methyl; intermediate—methylene; and most oxidized—formyl, formimino, and methenyl. The major donor of activated methyl groups is S-adenosylmethionine, which is synthesized by the transfer of an adenosyl group from ATP to the sulfur atom of methionine. S-Adenosylhomocysteine is formed when the activated methyl group is transferred to an acceptor. It is hydrolyzed to adenosine and homocysteine, the latter of which is then methylated to methionine to complete the activated methyl cycle.

Cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...

 inhibits protein synthesis.

Amino acid biosynthesis is regulated by feedback inhibition


Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from E. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications.

Amino acids are precursors of many biomolecules


Amino acids are precursors of a variety of biomolecules. Glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...

 (γ-Glu-Cys-Gly) serves as a sulfhydryl buffer and detoxifying agent. Glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...

, a selenoenzyme, catalyzes the reduction of hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

 and organic peroxides by glutathione. Nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

, a short-lived messenger, is formed from arginine. Porphyrins are synthesized from glycine and succinyl CoA, which condense to give δ-aminolevulinate. Two molecules of this intermediate become linked to form porphobilinogen
Porphobilinogen
Porphobilinogen is a pyrrole involved in porphyrin metabolism.It is generated by aminolevulinate and the enzyme ALA dehydratase. PBG is then converted into hydroxymethyl bilane by the enzyme porphobilinogen deaminase, also known as hydroxymethylbilane synthase.Acute intermittent porphyria causes...

. Four molecules of porphobilinogen combine to form a linear tetrapyrrole
Tetrapyrrole
Tetrapyrroles are compounds containing four pyrrole rings. With the exception of corrin, the four pyrrole rings are interconnected through one-carbon bridges, in either a linear or a cyclic fashion...

, which cyclizes to uroporphyrinogen III. Oxidation and side-chain modifications lead to the synthesis of protoporphyrin IX, which acquires an iron atom to form heme.

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