Abstract

As obligate intracellular parasites, viruses rely on host cells for the building blocks of progeny viruses. Metabolites such as amino acids, nucleotides, and lipids are central to viral proteins, genomes, and envelopes, and the availability of these molecules can restrict or promote infection. Polyamines, comprised of putrescine, spermidine, and spermine in mammalian cells, are also critical for virus infection. Polyamines are small, positively charged molecules that function in transcription, translation, and cell cycling. Initial work on the function of polyamines in bacteriophage infection illuminated these molecules as critical to virus infection. In the decades since early virus-polyamine descriptions, work on diverse viruses continues to highlight a role for polyamines in viral processes, including genome packaging and viral enzymatic activity. On the host side, polyamines function in the response to virus infection. Thus, viruses and hosts compete for polyamines, which are a critical resource for both. Pharmacologically targeting polyamines, tipping the balance to favor the host and restrict virus replication, holds significant promise as a broad-spectrum antiviral strategy.

Highlights

  • Polyamines are small, abundant, flexible, biomolecules that consist of carbon chains containing amino groups that give them a positive charge at cellular pH

  • SAMDC, an enzyme that is crucial for the conversion of putrescine to spermidine and spermine is regulated by an upstream ORF, at which ribosomes pause prior to the stop codon, stalling scanning ribosomes from initiating the translation of SAMDC [2]

  • In addition to roles in polymerase activity, chikungunya virus (CHIKV), Zika virus (ZIKV), and hepatitis C virus (HCV) translation rely on polyamines, as DFMO-treated cells exhibited reduced viral translation [43,47]

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Summary

Polyamine Synthesis and Regulation

Polyamines are small, abundant, flexible, biomolecules that consist of carbon chains containing amino groups that give them a positive charge at cellular pH. Putrescine is converted to spermidine via spermidine synthase (SRM) followed by conversion to spermine via spermine synthase (SMS). Spermine and spermidine can be catabolized back to putrescine by the addition of an acetyl group by spermidine/spermine acetyltransferase (SAT1) followed by polyamine oxidase (PAOX). SAMDC, an enzyme that is crucial for the conversion of putrescine to spermidine and spermine is regulated by an upstream ORF (uORF), at which ribosomes pause prior to the stop codon, stalling scanning ribosomes from initiating the translation of SAMDC [2]. Putrescine, spermidine, and spermine all play key roles in a wide variety of cellular processes (FiguPruet2re).sciDnue,estpoertmheiidrinche,aargned, stpheerymbiinnedanllupcllaeyickaecyidrsolaess wineallwasidaeffveacrtiecthyroomf caetlilnulsatrrupcrtoucreess[e6s]. Aaudtdopithioangaylliyn, pBocleylalsm[i1n2e]sarnedguthlaeteexmpermesbsiroanneofflouxididitayt:ivpeopsihtoivseplhyocrhyalargtieodn pporolyteaimnsiniensminatcerroapcthwagieths [n1e3g]a. tAivdedlyitciohnaarglleyd, ppohloysapmhoinliepsidrehgeualdagteromuepms tborarendeufcleuildipitiyd:mpoovsietmiveenlyt.cPhoalrygaemdipneoslyaalsmoirneegsuilnatteeriaocnt wchiathnnneel gfuanticvteiolyn, cphraortgeiend–RpNhAosipnhteorlaipcitdionhse,aadngdroceulpl jsuntoctiroendsu, caemolinpgidotmheorvs.emAlelnotf. tPhoeslyeacmritiinceasl raollseos wreigtuhilnatethieocnelclhaarnenaelsl ofucnructciioanl ,foprrvoitreuins–iRnfNecAtioinnt,esruagctgioesntsin, gantdhactetlhlejsuenmctioolnecsu, laems othnagt aorteheimrsp. oArltlanoft tfhoersceelclruiltaicraflurnoclteisonwsitahlsino tphleaycerlollaerseinalvsoirucrsuicnifaelcftoiornv.irus infection, suggesting that these molecules that are important for cellular functions play roles in virus infection

Polyamines in Bacteriophages
Polyamines in Plant Viruses and the Response to Infection
Polyamines in Mammalian Viruses and the Response to Infection
Polyamines in Metabolic Pathways Key to Virus Infection
Targeting Polyamines as an Antiviral Therapy
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