:5-Aminoimidazole ribotide

5-aminoimidazole derivatives were considered unstable and therefore difficult to synthesize. The first non-enzymatic synthesis of 5-aminoimidazole ribotide (AIR) was only published in 1988{{cite journal |doi=10.1073/pnas.85.19.7174 |title=Nonenzymatic synthesis of 5-aminoimidazole ribonucleoside and recognition of its facile rearrangement |year=1988 |last1=Groziak |first1=M. P. |last2=Bhat |first2=B. |last3=Leonard |first3=N. J. |journal=Proceedings of the National Academy of Sciences |volume=85 |issue=19 |pages=7174–7176 |pmid=3174626 |pmc=282146 |bibcode=1988PNAS...85.7174G |doi-access=free }} and general methodology for other examples was developed in the 1990s.{{cite journal |doi=10.1039/P19920002779 |title=Preparation, structure and addition reactions of 4- and 5-aminoimidazoles |year=1992 |last1=Al-Shaar |first1=Adnan H. M. |last2=Gilmour |first2=David W. |last3=Lythgoe |first3=David J. |last4=McClenaghan |first4=Ian |last5=Ramsden |first5=Christopher A. |journal=Journal of the Chemical Society, Perkin Transactions 1 |issue=21 |pages=2779–2788 }}{{cite journal |doi=10.1039/P19920002789 |title=The synthesis of heterocycles via addition–elimination reactions of 4- and 5-aminoimidazoles |year=1992 |last1=Al-Shaar |first1=Adnan H. M. |last2=Chambers |first2=Robert K. |last3=Gilmour |first3=David W. |last4=Lythgoe |first4=David J. |last5=McClenaghan |first5=Ian |last6=Ramsden |first6=Christopher A. |journal=J. Chem. Soc., Perkin Trans. 1 |issue=21 |pages=2789–2811 }}

The furanose (5-carbon) sugar in AIR comes from the pentose phosphate pathway, which converts glucose (as its 6-phosphate derivative) into ribose 5-phosphate (R5P).{{cite journal |last1=Alfarouk |first1=Khalid O. |last2=Ahmed |first2=Samrein B. M. |last3=Elliott |first3=Robert L. |last4=Benoit |first4=Amanda |last5=Alqahtani |first5=Saad S. |last6=Ibrahim |first6=Muntaser E. |last7=Bashir |first7=Adil H. H. |last8=Alhoufie |first8=Sari T. S. |last9=Elhassan |first9=Gamal O. |last10=Wales |first10=Christian C. |last11=Schwartz |first11=Laurent H. |last12=Ali |first12=Heyam S. |last13=Ahmed |first13=Ahmed |last14=Forde |first14=Patrick F. |last15=Devesa |first15=Jesus |last16=Cardone |first16=Rosa A. |last17=Fais |first17=Stefano |last18=Harguindey |first18=Salvador |last19=Reshkin |first19=Stephan J. |title=The Pentose Phosphate Pathway Dynamics in Cancer and Its Dependency on Intracellular pH |journal=Metabolites |date=2020 |volume=10 |issue=7 |pages=285 |doi=10.3390/metabo10070285 |pmid=32664469 |pmc=7407102 |language=en|doi-access=free }} The subsequent reactions which attach the aminoimidazole portion of the molecule begin when R5P is activated as its pyrophosphate derivative, phosphoribosyl pyrophosphate (PRPP). This reaction is catalysed by ribose-phosphate diphosphokinase.{{cite journal |last1=Li |first1=Sheng |last2=Lu |first2=Yongcheng |last3=Peng |first3=Baozhen |last4=Ding |first4=Jianping | title = Crystal structure of human phosphoribosylpyrophosphate synthetase 1 reveals a novel allosteric site | journal = Biochemical Journal | volume = 401 | issue = 1 | pages = 39–47 |date=January 2007 | pmid = 16939420 | pmc = 1698673 | doi = 10.1042/BJ20061066 }}

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Five biosynthetic steps complete the transformation.{{cite journal |doi=10.1007/s00018-008-8295-8 |last1=Zhang |first1=Y. |last2=Morar |first2=M. |last3=Ealick |first3=S.E. |title=Structural biology of the purine biosynthetic pathway |journal=Cellular and Molecular Life Sciences |volume=65 |pages=3699–3724 |year=2008 |issue=23 |pmid=18712276 |pmc=2596281 }} The first enzyme, amidophosphoribosyltransferase, attaches ammonia from glutamine to the ribotide at its anomeric carbon, forming phosphoribosylamine (PRA):

: {{chem|PRPP}} + {{chem|glutamine}} → {{chem|PRA}} + {{chem|glutamate}} + PPi

Next, PRA is converted to glycineamide ribonucleotide (GAR) by the action of phosphoribosylamine—glycine ligase, forming an amide bond with glycine in a process driven by ATP:

: {{chem|PRA}} + {{chem|glycine}} + ATP → {{chem|GAR}} + ADP + Pi

A third enzyme, phosphoribosylglycinamide formyltransferase, adds a formyl group from 10-formyltetrahydrofolate to GAR, giving phosphoribosyl-N-formylglycineamide (FGAR):

:GAR + 10-formyltetrahydrofolate → FGAR + tetrahydrofolate

The penultimate step converts FGAR to an amidine by the action of phosphoribosylformylglycinamidine synthase, transferring an amino group from glutamine and giving 5′-phosphoribosylformylglycinamidine (FGAM) in a reaction that also requires ATP:

:FGAR + ATP + glutamine + H₂O → FGAM + ADP + glutamate + Pi

FGAM is finally converted to AIR by the action of AIR synthetase which uses ATP to activate the terminal carbonyl group to attack by the nitrogen atom at the anomeric centre:

:FGAM + ATP → AIR + ADP + Pi + H⁺

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{{Main|Purine metabolism#Biosynthesis}}

The purine ring system of the nucleotide inosine monophosphate is formed in a pathway from AIR{{cite book |doi=10.1007/978-981-16-0723-3_19 |chapter=Nucleotide Biosynthesis and Regulation |title=Fundamentals of Bacterial Physiology and Metabolism |year=2021 |last1=Gupta |first1=Rani |last2=Gupta |first2=Namita |pages=525–554 |isbn=978-981-16-0722-6 |s2cid=234897784 }} that begins when phosphoribosylaminoimidazole carboxylase converts it to the carboxylated derivative in the imidazole ring, 5′-phosphoribosyl-4-carboxy-5-aminoimidazole (CAIR).{{cite journal |doi=10.1016/S0969-2126(00)80029-5 |last4=Ealick |first4=Steven E. |last3=Stubbe |first3=JoAnne |last2=Kappock |first2=T. Joseph |last1=Mathews |first1=Irimpan I. |title=Crystal structure of Escherichia coli PurE, an unusual mutase in the purine biosynthetic pathway |journal=Structure |volume=7 |issue=11 |pages=1395–1406 |year=1999 |pmid=10574791|doi-access=free }}

:AIR + CO₂ → CAIR + 2 H⁺

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The same compound can be formed in a two-step pathway when the enzymes involved are 5-(carboxyamino)imidazole ribonucleotide synthase and 5-(carboxyamino)imidazole ribonucleotide mutase.

Rearrangement reactions starting from AIR incorporate portions of the molecule into additional biochemical pathways. The enzymes involved are in the radical SAM superfamily of iron–sulfur proteins, which use S-adenosyl methionine as a cofactor to initiate the conversions via radical intermediates.{{cite book |doi=10.1016/bs.mie.2018.06.004 |chapter=Atlas of the Radical SAM Superfamily: Divergent Evolution of Function Using a "Plug and Play" Domain |title=Radical SAM Enzymes |series=Methods in Enzymology |year=2018 |last1=Holliday |first1=Gemma L. |last2=Akiva |first2=Eyal |last3=Meng |first3=Elaine C. |last4=Brown |first4=Shoshana D. |last5=Calhoun |first5=Sara |last6=Pieper |first6=Ursula |last7=Sali |first7=Andrej |last8=Booker |first8=Squire J. |last9=Babbitt |first9=Patricia C. |volume=606 |pages=1–71 |pmid=30097089 |pmc=6445391 |isbn=9780128127940 }}

The vitamin thiamine contains a pyrimidine ring system which is formed from AIR in a reaction catalysed by phosphomethylpyrimidine synthase.{{cite journal |doi=10.1039/C1NP00036E |title=Radical S-adenosylmethionine enzymes: Mechanism, control and function |year=2011 |last1=Challand |first1=Martin R. |last2=Driesener |first2=Rebecca C. |last3=Roach |first3=Peter L. |journal=Natural Product Reports |volume=28 |issue=10 |pages=1709–1710 |pmid=21779595 }}

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This reaction incorporates the blue, green and red fragments shown into the product, 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate.{{cite journal |doi=10.1039/b207131m |title=Cofactor biosynthesis: An organic chemist's treasure trove |year=2006 |last1=Begley |first1=Tadhg P. |journal=Natural Product Reports |volume=23 |issue=1 |pages=15–18 |pmid=16453030 }}

In some anaerobes, AIR is a precursor to 5,6-dimethylbenzimidazole, which is incorporated into vitamin B₁₂ in later steps of cobalamin biosynthesis.{{cite journal |doi=10.1126/science.aba0165 |title=Sharing vitamins: Cobamides unveil microbial interactions |year=2020 |last1=Sokolovskaya |first1=Olga M. |last2=Shelton |first2=Amanda N. |last3=Taga |first3=Michiko E. |journal=Science |volume=369 |issue=6499 |pmid=32631870 |pmc=8654454 }} The initial reaction is catalysed by 5-hydroxybenzimidazole synthase, {{EC number|4.1.99.23}}, and forms 5-hydroxybenzimidazole:

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All the carbon atoms of the product are transferred from AIR, as shown.

{{Reflist}}

{{Nucleotide metabolism intermediates}}

{{DEFAULTSORT:Aminoimidazole ribotide, 5-}}

Category:Nucleotides