Diadenosine tetraphosphate or Ap4A is a putative

alarmone An alarmone is an intracellular signal molecule that is produced in bacteria, chloroplasts, and a slim minority of archaea reacting to harsh environmental factors. They regulate the gene expression at transcription level. Alarmones are produced in ...

, ubiquitous in nature being common to everything from

bacteria Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were am ...

human Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedalism and exceptional cognitive skills due to a large and complex brain. This has enabled the development of advanced tools, cultu ...

s. It is made up of two adenosines joined together by a 5′-5′ linked chain of four phosphates. Adenosine polyphosphates are capable of inducing multiple

physiological Physiology (; ) is the scientific study of functions and mechanisms in a living system. As a sub-discipline of biology, physiology focuses on how organisms, organ systems, individual organs, cells, and biomolecules carry out the chemica ...

effects.

Function

In Eukaryotes

Ap4A can be created by a non-canonical activity of the Lysyl- tRNA synthetase (LysRS). This function of LysRS is activated by the phosphorylation of LysRS on serine 207, its subsequent dissociation from the multi-synthetase complex (MSC). The molecule's role as a second messenger has recently been discovered in The LysRS-Ap4A-

MITF Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the ''MITF'' gene. MITF is a basic helix-loop-helix leucine zipper transcription fact ...

signaling pathway. Ap4A binds to the MITF-HINT1 inhibitory complex, specifically to the molecule histidine triad nucleotide–binding protein 1(HINT1), releasing the Microphthalmia-associated transcription factor (MITF) and causing an increase in the transcription of its target genes. Ap4A also positively regulates the activity of the transcription factor USF2 through a similar molecular mechanism to that of MITF. It has also been shown, that Ap4A plays a role in the functionality of

dendritic cells Dendritic cells (DCs) are antigen-presenting cells (also known as ''accessory cells'') of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. The ...

(DCs). An increase in the intracellular amount Improves their motility and antigen presenting ability through alterations in small

GTPases GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...

present in the cells. This was discovered by creating mice deficient in the enzyme ''NUDT2,'' which serves as an Ap4A

hydrolase Hydrolase is a class of enzyme that commonly perform as biochemical catalysts that use water to break a chemical bond, which typically results in dividing a larger molecule into smaller molecules. Some common examples of hydrolase enzymes are este ...

and thus controls the levels of Ap4A in the cell. Ap4A, however, has also been shown to cause

apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...

in several cell lines through an unknown mechanism, the degradation of Ap4A was necessary for the process as hydrolysis‐resistant analogues of the molecule showed no apoptotic activity.

In Prokaryotes

In E. Coli, Ap4A has been shown to function as an alarmone, as the intracellular concentration of the molecule increases upon heat stress. Ap4A can also be incorporated into RNA as a

5' Cap In molecular biology, the five-prime cap (5′ cap) is a specially altered nucleotide on the 5′ end of some primary transcripts such as precursor messenger RNA. This process, known as mRNA capping, is highly regulated and vital in the creation ...

along with other dinucleoside polyphosphates. It serves as a substrate for the

RNA polymerase In molecular biology, RNA polymerase (abbreviated RNAP or RNApol), or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that synthesizes RNA from a DNA template. Using the enzyme helicase, RNAP locally opens th ...

and the intracellular levels of these capped RNAs increase upon stress, suggesting that the cap adds a level of stability to the RNA. ''

Myxococcus xanthus ''Myxococcus xanthus'' is a gram-negative, rod-shaped species of myxobacteria that exhibits various forms of self-organizing behavior in response to environmental cues. Under normal conditions with abundant food, it exists as a predatory, sapro ...

'' is a type of

Gram-negative bacteria Gram-negative bacteria are bacteria that do not retain the crystal violet stain used in the Gram staining method of bacterial differentiation. They are characterized by their cell envelopes, which are composed of a thin peptidoglycan cell wall ...

, and ''M. xanthus'' lysyl-tRNA synthetase (LysS) is an enzyme from the bacteria that synthesizes diadenosine tetraphosphates (Ap4A) when

adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms ...

(ATP) is present. Diadenosine pentaphosphate (Ap5A) is synthesized from Ap4A with ATP.

References

{{reflist RNA Nucleotides