Biosynthesis of pyrrolopyrimidines

Abstract

Pyrrolopyrimidine containing compounds, also known as 7-deazapurines, are a collection of purine-based metabolites that have been isolated from a variety of biological sources and have diverse functions which range from secondary metabolism to RNA modification. To date, nearly 35 compounds with the common 7-deazapurine core structure have been described. This article will illustrate the structural diversity of these compounds and review the current state of knowledge on the biosynthetic pathways that give rise to them.

Figure 1

Deazapurine-containing secondary metabolites isolated from terrestrial (1–12) and marine (13–29) sources.

Figure 2

Deazpaurines in tRNA. Queuosine and archaeosine analogs are found in the anticodon loop or the D-loop of tRNA, respectively. Archaeosine is only found in archaea. The site of glutamate esterificaion of glutamylqueusoine remains to be established.

Figure 3

Summary of radiotracer experiments for the conversion of guanosine to toyocamycin. In general, biosynthesis of all deazapurine-containing compounds from purines entails loss of carbon 8, retention of carbon 2, incorporation of carbons 1′ and 3′. In some cases, the 6-membered ring of the proferred purine undergoes further modifications. Refer to Figs 4, 5 and 7 for the specific reactions in the biosynthesis of toyocamycin.

Figure 4

Biosynthesis of preQ₀. Biosynthesis of 7-cyano-7-deazaguanine core of deazapurines from GTP is accomplished by the successive actions of GTP cyclohydrolase I (GCH I/ToyD), CPH₄ synthase (QueD/ToyB), CDG synthase (QueE/ToyC) and preQ₀ synthetase (QueC/ToyM). The loss of 3 carbon atoms by the successive actions of GCH I and QueD, elimination of a nitrogen by QueE and incorporation of ammonia by QueC have been demonstrated by high resolution mass spectrometry [56,62]. Loss of the nitrogen as ammonia from CPH₄ catalyzed by QueE has not been demonstrated explicitly.

Figure 5

Biosynthesis of queuosine. PreQ₀, synthesized as shown in Figure 4 is reduced by preQ₀ reductase (QueF), incorporated into tRNA by tRNA:guanine transglycosylase (TGT), and elaborated by epoxyqueuosine synthase (QueA) and oQ reductase (QueG) to the hypermodified base queuosine.

Figure 6

Biosynthesis of archaeosine. PreQ₀, synthesized as shown in Figure 4, is incorporated into RNA by the archaeal TGT (arcTGT) and elaborated by archaeosine synthase (ArcS) to archaeosine.

Figure 7

Biosynthesis of toyocamycin and sangivamycin from preQ₀. Dashed arrows denote hypothetical reactions that are based on sequence similarity. PreQ₀ is presumably converted to toyocamycin by the successive actions of ToyH, ToyE, ToyG, ToyF and ToyI. Toyocamycin nitrile hydratase (ToyJKL) catalyzes the conversion of toyocamycin to sangivamycin.