A polyamine is an organic compound having more than two amino groups. Alkyl polyamines occur naturally, but some are synthetic. Alkylpolyamines are colorless, hygroscopic, and water soluble. Near neutral pH, they exist as the ammonium derivatives. [1] Most aromatic polyamines are crystalline solids at room temperature.
Low-molecular-weight linear polyamines are found in all forms of life. The principal examples are the triamine spermidine and the tetraamine spermine. They are structurally and biosynthetically related to the diamines putrescine and cadaverine. Polyamine metabolism is regulated by the activity of the enzyme ornithine decarboxylase (ODC). [2] Polyamines are found in high concentrations in the mammalian brain. [3]
Ethyleneamines are a commercially-important class of synthetic polyamines with ethylene (−CH2CH2− linkages); global production capacity was estimated at 385,000 tonnes in 2001. [4] They are chemical intermediates often used to make surfactants and as crosslinkers for epoxy resins. [5] Some members of this class include:
Other synthetic polyamines include 1,3,5-triazinane (not to be confused with 1,3,5-triazine) and N-substituted analogs. The methylene (−CH2) linkages are derived from formaldehyde. The reaction product of monoethanolamine and formaldehyde is known industrially as "MEA triazine" (it is actually a triazinane), and it serves as a water-soluble hydrogen sulfide scavenger. [7] Hexamethylenetetramine (hexamine) is another product of formaldehyde and ammonia that has various uses in industry. Domestically, it is used as a solid camping fuel. In the laboratory, it reacts with alkyl halides to selectively prepare primary amines in the Delépine reaction.
Although it is known that the biosynthesis of polyamines is highly regulated, the biological function of polyamines is only partly understood. In their cationic ammonium form, they bind to DNA, and, in structure, they represent compounds with cations that are found at regularly spaced intervals (in contrast to Mg2+
or Ca2+
, which are point charges). They have also been found to act as promoters of programmed ribosomal frameshifting during translation. [8]
Inhibition of polyamine biosynthesis retards or stops cell growth. The provision of exogenous polyamines restores the growth of these cells. Most eukaryotic cells express a polyamine-transporting ATPase on their cell membrane that facilitates the internalization of exogenous polyamines. This system is highly active in rapidly proliferating cells and is the target of some chemotherapeutics currently under development. [9]
Polyamines are also modulators of a variety of ion channels, including NMDA receptors and AMPA receptors. They block inward-rectifier potassium channels so that the currents of the channels are inwardly rectified, thereby the cellular energy, i.e. K+
ion gradient across the cell membrane, is conserved. In addition, polyamine participate in initiating the expression of SOS response of Colicin E7 operon and down-regulate proteins that are essential for colicin E7 uptake, thus conferring a survival advantage on colicin-producing E. coli under stress conditions. [10]
Polyamines can enhance the permeability of the blood–brain barrier. [11]
They are involved in modulating senescence of organs in plants and are therefore considered as a plant hormone. [12] In addition, they are directly involved in regulation of programmed cell death. [13]
Polyamines promote homologous recombination (HR)-mediated double-strand break (DSB) repair. [14] Polyamines enhance the DNA strand exchange activity of RAD51 recombinase. Depletion of polyamines sensitizes cells to genotoxic substances such as ionizing radiation and ultraviolet radiation. The effect of polyamines on RAD51 arises from their ability to enhance the capture of homologous duplex DNA and promote RAD-51-mediated homologous DNA pairing and exchange activity. [14] Polyamines appear to have an evolutionarily conserved role in regulating recombinase activity.
Spermidine is synthesized from putrescine, using an aminopropyl group from decarboxylated S-adenosyl-L-methionine (SAM), S-Adenosylmethioninamine. The reaction is catalyzed by spermidine synthase. [15]
Spermine is synthesized from the reaction of spermidine with SAM in the presence of the enzyme spermine synthase.
The polyamines undergo rapid interconversion in the polyamine cycle, in which putrescine leads to synthesis of spermidine and spermine, with degradation of these polyamines to form putrescine, which can begin the cycle again. [15]
Thermospermine (NH2−(CH2)3−NH−(CH2)3−NH−(CH2)4−NH2) is a structural isomer of spermine and a plant growth regulator. It is produced from spermidine by the action of thermospermine synthase, which is encoded by a gene named ACAULIS5 (ACL5). [16]
The critical role of polyamines in cell growth has led to the development of a number of agents that interfere with polyamine metabolism. These agents are used in cancer therapy. Polyamine analogues upregulate p53 in a cell leading to restriction of proliferation and apoptosis. [17] It also decreases the expression of estrogen receptor alpha in ER-positive breast cancer. [18]
Putrescine is an organic compound with the formula (CH2)4(NH2)2. It is a colorless solid that melts near room temperature. It is classified as a diamine. Together with cadaverine, it is largely responsible for the foul odor of putrefying flesh, but also contributes to other unpleasant odors.
Cadaverine is an organic compound with the formula (CH2)5(NH2)2. Classified as a diamine, it is a colorless liquid with an unpleasant odor. It is present in small quantities in living organisms but is often associated with the putrefaction of animal tissue. Together with putrescine, it is largely responsible for the foul odor of putrefying flesh, but also contributes to other unpleasant odors.
The enzyme ornithine decarboxylase catalyzes the decarboxylation of ornithine to form putrescine. This reaction is the committed step in polyamine synthesis. In humans, this protein has 461 amino acids and forms a homodimer.
A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.
Agmatine, also known as 4-aminobutyl-guanidine, was discovered in 1910 by Albrecht Kossel. It is a chemical substance which is naturally created from the amino acid arginine. Agmatine has been shown to exert modulatory action at multiple molecular targets, notably: neurotransmitter systems, ion channels, nitric oxide (NO) synthesis, and polyamine metabolism and this provides bases for further research into potential applications.
Spermine is a polyamine involved in cellular metabolism that is found in all eukaryotic cells. The precursor for synthesis of spermine is the amino acid ornithine. It is an essential growth factor in some bacteria as well. It is found as a polycation at physiological pH. Spermine is associated with nucleic acids and is thought to stabilize helical structure, particularly in viruses. It functions as an intracellular free radical scavenger to protect DNA from free radical attack. Spermine is the chemical primarily responsible for the characteristic odor of semen.
Spermidine is a polyamine compound found in ribosomes and living tissues and having various metabolic functions within organisms.
Spermidine synthase is an enzyme that catalyzes the transfer of the propylamine group from S-adenosylmethioninamine to putrescine in the biosynthesis of spermidine. The systematic name is S-adenosyl 3-(methylthio)propylamine:putrescine 3-aminopropyltransferase and it belongs to the group of aminopropyl transferases. It does not need any cofactors. Most spermidine synthases exist in solution as dimers.
Spermine synthase is an enzyme that converts spermidine into spermine. This enzyme catalyses the following chemical reaction
A polyamine oxidase (PAO) is an enzymatic flavoprotein that oxidizes a carbon-nitrogen bond in a secondary amino group of a polyamine donor, using molecular oxygen as an acceptor. The generalized PAO reaction converts three substrates into three products. Different PAOs with varying substrate specificities exist in different organisms. Phylogenetic analyses suggest that PAOs likely evolved once in eukaryotes and diversified by divergent evolution and gene duplication events, though some prokaryotes have acquired PAOs through horizontal gene transfer.
Flavin-containing amine oxidoreductases are a family of various amine oxidases, including maize polyamine oxidase (PAO), L-amino acid oxidases (LAO) and various flavin containing monoamine oxidases (MAO). The aligned region includes the flavin binding site of these enzymes. In vertebrates, MAO plays an important role in regulating the intracellular levels of amines via their oxidation; these include various neurotransmitters, neurotoxins and trace amines. In lower eukaryotes such as aspergillus and in bacteria the main role of amine oxidases is to provide a source of ammonium. PAOs in plants, bacteria and protozoa oxidise spermidine and spermine to an aminobutyral, diaminopropane and hydrogen peroxide and are involved in the catabolism of polyamines. Other members of this family include tryptophan 2-monooxygenase, putrescine oxidase, corticosteroid-binding proteins, and antibacterial glycoproteins.
Diamine acetyltransferase 1 is an enzyme that in humans is encoded by the SAT1 gene found on the X chromosome.
Polyamine-modulated factor 1 is a protein that in humans is encoded by the PMF1 gene.
Spermine synthase is an enzyme that in humans is encoded by the SMS gene. The protein encoded by this gene belongs to the spermidine/spermine synthases family. This gene encodes a ubiquitous enzyme of polyamine metabolism.
Peroxisomal N(1)-acetyl-spermine/spermidine oxidase is an enzyme that in humans is encoded by the PAOX gene.
Diamine acetyltransferase 2 is an enzyme that in humans is encoded by the SAT2 gene. SAT2 maintains a key metabolic glutamine/glutamate balance underpinning retrograde signaling by dendritic release of the neurotransmitter glutamate.
A ureohydrolase is a type of hydrolase enzyme. The ureohydrolase superfamily includes arginase, agmatinase, formiminoglutamase and proclavaminate amidinohydrolase. These enzymes share a 3-layer alpha-beta-alpha structure, and play important roles in arginine/agmatine metabolism, the urea cycle, histidine degradation, and other pathways.
S-Adenosylmethioninamine is a substrate that is required for the biosynthesis of polyamines including spermidine, spermine, and thermospermine. It is produced by decarboxylation of S-adenosyl methionine.
Non-specific polyamine oxidase (EC 1.5.3.17, polyamine oxidase, Fms1, AtPAO3) is an enzyme with systematic name polyamine:oxygen oxidoreductase (3-aminopropanal or 3-acetamidopropanal-forming). This enzyme catalyses the following chemical reaction
Polyamines (PAs) are small, positively charged, organic molecules that are ubiquitous in all living organisms. These are considered as one of the oldest group of substances known in biochemistry. There are three common types of polyamines, putrescine, spermidine, hermospermine according to structure, universal distribution in all cellular compartments, and presumed involvement in physiological activities. Polyamine is found in all cellular compartments and physiological activities due to their simple structures. The function of polyamine is very diverse in that it performs a key macromolecule to cellular membrane. Because of their essential roles in plant, mutation of polyamines can cause critical damage on plants. Furthermore, some polyamines like putrescine inhibit biosynthetic activities in plants. The activity of polyamines can be categorized to some parts due to its signalling and growing activity.
