Crystal structures of Apo and GMP bound hypoxanthine–guanine phosphoribosyltransferase from Legionella pneumophila and the implications in gouty arthritis

Zhang, Nannan; Gong, Xiaojian; Lu, Min; Chen, Xiaofang; Qin, Ximing; Ge, Honghua

doi:10.1016/j.jsb.2016.03.007

Cited by 7 publications

(6 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, genome sequence analysis of L. sordida mycelia showed that the fungus has other genes encoding phosphoribosyltransferases . Generally, the substrate specificity of phosphoribosyltransferases such as APRT and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is different from each other and the enzymes recognize different compounds having a purine-like skeleton as substrates. , Therefore, AHX and AOH might be metabolized to their ribotides by other phosphoribosyltransferases such as HGPRT in L. sordida mycelia.…”

Section: Resultsmentioning

confidence: 99%

Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida

Ito

Choi²,

Takemura

et al. 2020

J. Nat. Prod.

View full text Add to dashboard Cite

Fairy rings resulting from a fungus−plant interaction appear worldwide. 2-Azahypoxanthine (AHX) and imidazole-4-carboxamide (ICA) were first isolated from the culture broth of one of the fairy ring-forming fungi, Lepista sordida. Afterward, a common metabolite of AHX in plants, 2-aza-8-oxohypoxanthine (AOH), was found in AHX-treated rice. The biosynthetic pathway of the three compounds that are named as fairy chemicals (FCs) in plants has been partially elucidated; however, that in mushrooms remains unknown. In this study, it was revealed that the carbon skeletons of AHX and ICA were constructed from Gly in L. sordida mycelia and the fungus metabolized 5-aminoimidazole-4-carboxamide (AICA) to both of the compounds. These results indicated that FCs were biosynthesized by a diversion of the purine metabolic pathway in L. sordida mycelia, similar to that in plants. Furthermore, we showed that recombinant adenine phosphoribosyltransferase (APRT) catalyzed reversible interconversion not only between 5aminoimidazole-4-carboxamide-1-β-D-ribofuranosyl 5′-monophosphate (AICAR) and AICA but also between ICA-ribotide (ICAR) and ICA. Furthermore, the presence of ICAR in L. sordida mycelia was proven for the first time by LC-MS/MS detection, and this study provided the first report that there was a novel metabolic pathway of ICA in which its ribotide was an intermediate in the fungus.

show abstract

Section: Resultsmentioning

confidence: 99%

Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida

Ito

Choi²,

Takemura

et al. 2020

J. Nat. Prod.

View full text Add to dashboard Cite

show abstract

“…PRPP = phosphoribosyl pyrophosphate. a obtained with hypoxanthine as the purine base. b Guddat et al (2002). c Zhang et al (2016). d Patta et al (2015). ± standard error.…”

Section: Resultsmentioning

confidence: 99%

“…The structural basis of how the dimer–dimer interaction promotes (p)ppGpp binding in tetrameric HPRTs can be seen from comparative structures of apo B. anthracis Hpt-1 and apo L. pneumophila HPRT (PDB ID 5ESW) (Zhang et al, 2016). Loop II in dimeric L. pneumophila HPRT is positioned closer to the active site (Figure 5B), mimicking substrates-bound HPRT even in the absence of substrates (Figure 5—figure supplement 1), and compresses the cavity surrounding the 5′ phosphates of ppGpp (Figure 5C).…”

Section: Resultsmentioning

confidence: 99%

“…HPRT tetramerization also affects a key component of basal (p)ppGpp’s ability to regulate HPRT: its competition with PRPP. Most bacterial HPRTs have a K m for PRPP in the range of 50–200 μM (Guddat et al, 2002; Zhang et al, 2016) (Table 4). Tetrameric HPRTs that bind (p)ppGpp with high affinity also tend to have higher K m values for PRPP, suggesting that they are optimized for (p)ppGpp binding rather than PRPP binding (Table 4).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction

Anderson

Liu

Wolak

et al. 2019

eLife

View full text Add to dashboard Cite

The alarmone (p)ppGpp regulates diverse targets, yet its target specificity and evolution remain poorly understood. Here, we elucidate the mechanism by which basal (p)ppGpp inhibits the purine salvage enzyme HPRT by sharing a conserved motif with its substrate PRPP. Intriguingly, HPRT regulation by (p)ppGpp varies across organisms and correlates with HPRT oligomeric forms. (p)ppGpp-sensitive HPRT exists as a PRPP-bound dimer or an apo- and (p)ppGpp-bound tetramer, where a dimer-dimer interface triggers allosteric structural rearrangements to enhance (p)ppGpp inhibition. Loss of this oligomeric interface results in weakened (p)ppGpp regulation. Our results reveal an evolutionary principle whereby protein oligomerization allows evolutionary change to accumulate away from a conserved binding pocket to allosterically alter specificity of ligand interaction. This principle also explains how another (p)ppGpp target GMK is variably regulated across species. Since most ligands bind near protein interfaces, we propose that this principle extends to many other protein–ligand interactions.

show abstract

“…This suggests that the active site, as well as the base‐binding domain of this enzyme, is pre‐formed to accommodate the substrates. Conversely, the base‐binding loop of 6‐oxopurine PRTases is generally stabilized only upon substrate binding, even though the core PRPP binding domain is observed to be similar in both the apo and substrate‐bound forms . Probably, this flexibility of the base‐binding loop is a requirement considering its promiscuous recognition of all the three 6‐oxopurines (guanine, xanthine and hypoxanthine).…”

Section: Resultsmentioning

confidence: 99%

Crystal structures of APRT from Francisella tularensis – an N–H···N hydrogen bond imparts adenine specificity in adenine phosporibosyltransferases

Pavithra

Ramagopal

2018

The FEBS Journal

View full text Add to dashboard Cite

show abstract

Crystal structures of Apo and GMP bound hypoxanthine–guanine phosphoribosyltransferase from Legionella pneumophila and the implications in gouty arthritis

Cited by 7 publications

References 36 publications

Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida

Biosynthesis of the Fairy Chemicals, 2-Azahypoxanthine and Imidazole-4-carboxamide, in the Fairy Ring-Forming Fungus Lepista sordida

Evolution of (p)ppGpp-HPRT regulation through diversification of an allosteric oligomeric interaction

Crystal structures of APRT from Francisella tularensis – an N–H···N hydrogen bond imparts adenine specificity in adenine phosporibosyltransferases

Contact Info

Product

Resources

About