Alanine

Last updated
Alanine
L-Alanin - L-Alanine.svg
Skeletal formula of L-alanine (neutral form)
Alanine-from-xtal-3D-bs-17.png
Ball-and-stick model (zwitterionic form)
L-alanine-from-xtal-Mercury-3D-sf.png
Space-filling model (zwitterionic form)
Names
IUPAC name
Alanine [1]
Preferred IUPAC name
2-Aminopropanoic acid
Identifiers
3D model (JSmol)
3DMet
1720248
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.249 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • L:206-126-4
49628
KEGG
PubChem CID
UNII
  • InChI=1S/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1
    Key: QNAYBMKLOCPYGJ-REOHCLBHSA-N Yes check.svgY
  • D/L:Key: QNAYBMKLOCPYGJ-UHFFFAOYSA-N
  • D:Key: QNAYBMKLOCPYGJ-UWTATZPHSA-N
  • L:C[C@@H](C(=O)O)N
  • L Zwitterion:C[C@@H](C(=O)[O-])[NH3+]
Properties
C3H7NO2
Molar mass 89.094 g·mol−1
Appearancewhite powder
Density 1.424 g/cm3
Melting point 258 °C (496 °F; 531 K) (sublimes)
167.2 g/L (25 °C)
log P -0.68 [2]
Acidity (pKa)
  • 2.34 (carboxyl; H2O)
  • 9.87 (amino; H2O) [3]
-50.5·10−6 cm3/mol
Supplementary data page
Alanine (data page)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Alanine (symbol Ala or A), [4] or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side chain. Consequently, its IUPAC systematic name is 2-aminopropanoic acid, and it is classified as a nonpolar, aliphatic α-amino acid. Under biological conditions, it exists in its zwitterionic form with its amine group protonated (as −NH3+) and its carboxyl group deprotonated (as −CO2). It is non-essential to humans as it can be synthesised metabolically and does not need to be present in the diet. It is encoded by all codons starting with GC (GCU, GCC, GCA, and GCG).

Contents

The L-isomer of alanine (left-handed) is the one that is incorporated into proteins. L-alanine is second only to leucine in rate of occurrence, accounting for 7.8% of the primary structure in a sample of 1,150 proteins. [5] The right-handed form, D-alanine, occurs in polypeptides in some bacterial cell walls [6] :131 and in some peptide antibiotics, and occurs in the tissues of many crustaceans and molluscs as an osmolyte. [7]

History and etymology

Alanine was first synthesized in 1850 when Adolph Strecker combined acetaldehyde and ammonia with hydrogen cyanide. [8] [9] [10] The amino acid was named Alanin in German, in reference to aldehyde, with the infix -an- for ease of pronunciation, [11] the German ending -in used in chemical compounds being analogous to English -ine .

Structure

Alanine is an aliphatic amino acid, because the side-chain connected to the α-carbon atom is a methyl group (-CH3); alanine is the simplest α-amino acid after glycine. The methyl side-chain of alanine is non-reactive and is therefore hardly ever directly involved in protein function. [12] Alanine is a nonessential amino acid, meaning it can be manufactured by the human body, and does not need to be obtained through the diet. Alanine is found in a wide variety of foods, but is particularly concentrated in meats.

Sources

Biosynthesis

Alanine can be synthesized from pyruvate and branched chain amino acids such as valine, leucine, and isoleucine.

Alanine is produced by reductive amination of pyruvate, a two-step process. In the first step, α-ketoglutarate, ammonia and NADH are converted by glutamate dehydrogenase to glutamate, NAD+ and water. In the second step, the amino group of the newly-formed glutamate is transferred to pyruvate by an aminotransferase enzyme, regenerating the α-ketoglutarate, and converting the pyruvate to alanine. The net result is that pyruvate and ammonia are converted to alanine, consuming one reducing equivalent. [6] :721 Because transamination reactions are readily reversible and pyruvate is present in all cells, alanine can be easily formed and thus has close links to metabolic pathways such as glycolysis, gluconeogenesis, and the citric acid cycle.

Chemical synthesis

L-Alanine is produced industrially by decarboxylation of L-aspartate by the action of aspartate 4-decarboxylase. Fermentation routes to L-alanine are complicated by alanine racemase. [13]

Racemic alanine can be prepared by the condensation of acetaldehyde with ammonium chloride in the presence of sodium cyanide by the Strecker reaction, [14] or by the ammonolysis of 2-bromopropanoic acid. [15]

Synthesis of alanine - 1.png
Synthesis of alanine - 2.png

Degradation

Alanine is broken down by oxidative deamination, the inverse reaction of the reductive amination reaction described above, catalyzed by the same enzymes. The direction of the process is largely controlled by the relative concentration of the substrates and products of the reactions involved. [6] :721

Alanine World Hypothesis

Alanine is one of the twenty canonical α-amino acids used as building blocks (monomers) for the ribosome-mediated biosynthesis of proteins. Alanine is believed to be one of the earliest amino acids to be included in the genetic code standard repertoire. [16] [17] [18] [19] On the basis of this fact the "Alanine World" hypothesis was proposed. [20] This hypothesis explains the evolutionary choice of amino acids in the repertoire of the genetic code from a chemical point of view. In this model the selection of monomers (i.e. amino acids) for ribosomal protein synthesis is rather limited to those Alanine derivatives that are suitable for building α-helix or β-sheet secondary structural elements. Dominant secondary structures in life as we know it are α-helices and β-sheets and most canonical amino acids can be regarded as chemical derivatives of Alanine. Therefore, most canonical amino acids in proteins can be exchanged with Ala by point mutations while the secondary structure remains intact. The fact that Ala mimics the secondary structure preferences of the majority of the encoded amino acids is practically exploited in alanine scanning mutagenesis. In addition, classical X-ray crystallography often employs the polyalanine-backbone model [21] to determine three-dimensional structures of proteins using molecular replacement - a model-based phasing method.

Physiological function

Glucose–alanine cycle

In mammals, alanine plays a key role in glucose–alanine cycle between tissues and liver. In muscle and other tissues that degrade amino acids for fuel, amino groups are collected in the form of glutamate by transamination. Glutamate can then transfer its amino group to pyruvate, a product of muscle glycolysis, through the action of alanine aminotransferase, forming alanine and α-ketoglutarate. The alanine enters the bloodstream, and is transported to the liver. The alanine aminotransferase reaction takes place in reverse in the liver, where the regenerated pyruvate is used in gluconeogenesis, forming glucose which returns to the muscles through the circulation system. Glutamate in the liver enters mitochondria and is broken down by glutamate dehydrogenase into α-ketoglutarate and ammonium, which in turn participates in the urea cycle to form urea which is excreted through the kidneys. [22]

The glucose–alanine cycle enables pyruvate and glutamate to be removed from muscle and safely transported to the liver. Once there, pyruvate is used to regenerate glucose, after which the glucose returns to muscle to be metabolized for energy: this moves the energetic burden of gluconeogenesis to the liver instead of the muscle, and all available ATP in the muscle can be devoted to muscle contraction. [22] It is a catabolic pathway, and relies upon protein breakdown in the muscle tissue. Whether and to what extent it occurs in non-mammals is unclear. [23] [24]

Alterations in the alanine cycle that increase the levels of serum alanine aminotransferase (ALT) are linked to the development of type II diabetes. [25]

Chemical properties

(S)-Alanine (left) and (R)-alanine (right) in zwitterionic form at neutral pH Zwitterion-Alanine.png
(S)-Alanine (left) and (R)-alanine (right) in zwitterionic form at neutral pH

Alanine is useful in loss of function experiments with respect to phosphorylation. Some techniques involve creating a library of genes, each of which has a point mutation at a different position in the area of interest, sometimes even every position in the whole gene: this is called "scanning mutagenesis". The simplest method, and the first to have been used, is so-called alanine scanning, where every position in turn is mutated to alanine. [26]

Hydrogenation of alanine gives the amino alcohol alaninol, which is a useful chiral building block.

Free radical

The deamination of an alanine molecule produces the free radical CH3CHCO2. Deamination can be induced in solid or aqueous alanine by radiation that causes homolytic cleavage of the carbonnitrogen bond. [27]

This property of alanine is used in dosimetric measurements in radiotherapy. When normal alanine is irradiated, the radiation causes certain alanine molecules to become free radicals, and, as these radicals are stable, the free radical content can later be measured by electron paramagnetic resonance in order to find out how much radiation the alanine was exposed to. [28] This is considered to be a biologically relevant measure of the amount of radiation damage that living tissue would suffer under the same radiation exposure. [28] Radiotherapy treatment plans can be delivered in test mode to alanine pellets, which can then be measured to check that the intended pattern of radiation dose is correctly delivered by the treatment system.

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Metabolic pathway

The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle —is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The Krebs cycle is used by organisms that respire to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism and may have originated abiogenically. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

α-Ketoglutaric acid Chemical compound

α-Ketoglutaric acid is one of two ketone derivatives of glutaric acid. The term "ketoglutaric acid," when not further qualified, almost always refers to the alpha variant. β-Ketoglutaric acid varies only by the position of the ketone functional group, and is much less common.

<span class="mw-page-title-main">Glutamic acid</span> Amino acid and neurotransmitter

Glutamic acid is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synthesize enough for its use. It is also the most abundant excitatory neurotransmitter in the vertebrate nervous system. It serves as the precursor for the synthesis of the inhibitory gamma-aminobutyric acid (GABA) in GABA-ergic neurons.

In molecular biology, protein catabolism is the breakdown of proteins into smaller peptides and ultimately into amino acids. Protein catabolism is a key function of digestion process. Protein catabolism often begins with pepsin, which converts proteins into polypeptides. These polypeptides are then further degraded. In humans, the pancreatic proteases include trypsin, chymotrypsin, and other enzymes. In the intestine, the small peptides are broken down into amino acids that can be absorbed into the bloodstream. These absorbed amino acids can then undergo amino acid catabolism, where they are utilized as an energy source or as precursors to new proteins.

Anabolism is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-down aspect. Anabolism is usually synonymous with biosynthesis.

Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Alanine transaminase</span> Mammalian protein

Alanine transaminase (ALT) is a transaminase enzyme. It is also called alanine aminotransferase and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first characterized in the mid-1950s by Arthur Karmen and colleagues. ALT is found in plasma and in various body tissues but is most common in the liver. It catalyzes the two parts of the alanine cycle. Serum ALT level, serum AST level, and their ratio are commonly measured clinically as biomarkers for liver health. The tests are part of blood panels.

<span class="mw-page-title-main">Transamination</span>

Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential amino acids to non-essential amino acids.

<span class="mw-page-title-main">Aspartate transaminase</span> Enzyme involved in amino acid metabolism

Aspartate transaminase (AST) or aspartate aminotransferase, also known as AspAT/ASAT/AAT or (serum) glutamic oxaloacetic transaminase, is a pyridoxal phosphate (PLP)-dependent transaminase enzyme that was first described by Arthur Karmen and colleagues in 1954. AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in amino acid metabolism. AST is found in the liver, heart, skeletal muscle, kidneys, brain, red blood cells and gall bladder. Serum AST level, serum ALT level, and their ratio are commonly measured clinically as biomarkers for liver health. The tests are part of blood panels.

<span class="mw-page-title-main">Glutamate dehydrogenase</span> Hexameric enzyme

Glutamate dehydrogenase is an enzyme observed in both prokaryotes and eukaryotic mitochondria. The aforementioned reaction also yields ammonia, which in eukaryotes is canonically processed as a substrate in the urea cycle. Typically, the α-ketoglutarate to glutamate reaction does not occur in mammals, as glutamate dehydrogenase equilibrium favours the production of ammonia and α-ketoglutarate. Glutamate dehydrogenase also has a very low affinity for ammonia, and therefore toxic levels of ammonia would have to be present in the body for the reverse reaction to proceed. However, in brain, the NAD+/NADH ratio in brain mitochondria encourages oxidative deamination. In bacteria, the ammonia is assimilated to amino acids via glutamate and aminotransferases. In plants, the enzyme can work in either direction depending on environment and stress. Transgenic plants expressing microbial GLDHs are improved in tolerance to herbicide, water deficit, and pathogen infections. They are more nutritionally valuable.

<span class="mw-page-title-main">Transaminase</span> Class of enzymes

Transaminases or aminotransferases are enzymes that catalyze a transamination reaction between an amino acid and an α-keto acid. They are important in the synthesis of amino acids, which form proteins.

<span class="mw-page-title-main">Cahill cycle</span> Metabolic pathway for transport of energy into and removal of ammonia from muscles

The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients between skeletal muscle and the liver. When muscles degrade amino acids for energy needs, the resulting nitrogen is transaminated to pyruvate to form alanine. This is performed by the enzyme alanine transaminase (ALT), which converts L-glutamate and pyruvate into α-ketoglutarate and L-alanine. The resulting L-alanine is shuttled to the liver where the nitrogen enters the urea cycle and the pyruvate is used to make glucose.

<span class="mw-page-title-main">Amino acid synthesis</span> The set of biochemical processes by which amino acids are produced

Amino acid synthesis is the set of biochemical processes by which the amino acids are produced. The substrates for these processes are various compounds in the organism's diet or growth media. Not all organisms are able to synthesize all amino acids. For example, humans can synthesize 11 of the 20 standard amino acids.

Oxidative deamination is a form of deamination that generates α-keto acids and other oxidized products from amine-containing compounds, and occurs primarily in the liver. Oxidative deamination is stereospecific, meaning it contains different stereoisomers as reactants and products; this process is either catalyzed by L or D- amino acid oxidase and L-amino acid oxidase is present only in the liver and kidney. Oxidative deamination is an important step in the catabolism of amino acids, generating a more metabolizable form of the amino acid, and also generating ammonia as a toxic byproduct. The ammonia generated in this process can then be neutralized into urea via the urea cycle.

<span class="mw-page-title-main">Serine dehydratase</span>

Serine dehydratase or L-serine ammonia lyase (SDH) is in the β-family of pyridoxal phosphate-dependent (PLP) enzymes. SDH is found widely in nature, but its structural and properties vary among species. SDH is found in yeast, bacteria, and the cytoplasm of mammalian hepatocytes. SDH catalyzes is the deamination of L-serine to yield pyruvate, with the release of ammonia.

The glutamate–glutamine cycle in biochemistry, is a sequence of events by which an adequate supply of the neurotransmitter glutamate is maintained in the central nervous system. Neurons are unable to synthesize either the excitatory neurotransmitter glutamate, or the inhibitory GABA from glucose. Discoveries of glutamate and glutamine pools within intercellular compartments led to suggestions of the glutamate–glutamine cycle working between neurons and astrocytes. The glutamate/GABA–glutamine cycle is a metabolic pathway that describes the release of either glutamate or GABA from neurons which is then taken up into astrocytes. In return, astrocytes release glutamine to be taken up into neurons for use as a precursor to the synthesis of either glutamate or GABA.

<span class="mw-page-title-main">Glyceroneogenesis</span>

Glyceroneogenesis is a metabolic pathway which synthesizes glycerol 3-phosphate or triglyceride from precursors other than glucose. Usually glycerol 3-phosphate is generated from glucose by glycolysis, but when glucose concentration drops in the cytosol, it is generated by another pathway called glyceroneogenesis. Glyceroneogenesis uses pyruvate, alanine, glutamine or any substances from the TCA cycle as precursors for glycerol 3-phosphate. Phosphoenolpyruvate carboxykinase (PEPC-K), which is an enzyme that catalyzes the decarboxylation of oxaloacetate to phosphoenolpyruvate is the main regulator for this pathway. Glyceroneogenesis can be observed in adipose tissue and also liver. It is a significant biochemical pathway which regulates cytosolic lipid levels. Intense suppression of glyceroneogenesis may lead to metabolic disorder such as type 2 diabetes.

The purine nucleotide cycle is a metabolic pathway in which ammonia and fumarate are generated from aspartate and inosine monophosphate (IMP) to regulate the levels of adenine nucleotides, and to facilitate the liberation of ammonia from amino acids. Lowenstein first described this pathway and outlined its importance in processes including amino acid catabolism and regulation of flux through glycolysis and the Krebs cycle.

<span class="mw-page-title-main">Glutamic--pyruvic transaminase 2</span> Protein-coding gene in the species Homo sapiens

Glutamic--pyruvic transaminase 2 is a protein that in humans is encoded by the GPT2 gene.

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