Structural analysis of a phosphonate hydroxylase with an access tunnel at the back of the active site

Li, Changqing; Junaid, Muhammad; Almuqri, Eman Abdullah; Hao, Shiguang; Zhang, Houjin

doi:10.1107/s2053230x16004933

Cited by 6 publications

(10 citation statements)

References 26 publications

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“…The synthesis of selected phosphonate-containing antibiotics also involves hydroxylases. For example, the structurally characterized FrbJ from Streptomyces rubellomurinus [67] catalyzes a reaction (Figure 3D) yielding the anti-malarial compound FR-33289. Similarly, FzmG from Streptomyces lavendofoliae catalyzes two hydroxylation reactions (Figure 3E and 3F) during the synthesis of fosfazinomycin, an anti-fungal compound [68].…”

Section: Roles Of 2og-dependent Oxygenases In Biosynthesismentioning

confidence: 99%

Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases

Herr

Hausinger

2018

Trends in Biochemical Sciences

170

173

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Since their discovery in the 1960s, the family of Fe(II)/2-oxoglutarate-dependent oxygenases has undergone a tremendous expansion to include enzymes catalyzing a vast diversity of biologically important reactions. Recent examples highlight roles in controlling chromatin modification, transcription, mRNA demethylation, and mRNA splicing. Others generate modifications in tRNA, translation factors, ribosomes, and other proteins. Thus, oxygenases affect all components of molecular biology's central dogma, in which information flows from DNA to RNA to proteins. These enzymes also function in biosynthesis and catabolism of cellular metabolites, including antibiotics and signaling molecules. Due to their critical importance, ongoing efforts have targeted family members for the development of specific therapeutics. This review provides a general overview of recently characterized oxygenase reactions and their key biological roles.

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Section: Roles Of 2og-dependent Oxygenases In Biosynthesismentioning

confidence: 99%

Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases

Herr

Hausinger

2018

Trends in Biochemical Sciences

170

173

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“…However, identification of biosynthetic gene cluster for 12c would be necessary to test this hypothesis. An X-ray crystal structure of apo-FrbJ was recently reported . Comparison of FrbJ with the structure of TauD, which performs α-hydroxylation of taurine 50 , identified the conserved Fe(II) binding triad of H150, H288, and D152, as well as the α-ketoglutarate binding residues R290 and R309.…”

Section: Pathways For Synthesizing Complex Pn Natural Productsmentioning

confidence: 99%

“…An X-ray crystal structure of apo-FrbJ was recently reported. 407 Comparison of FrbJ with the structure of TauD, which performs α-hydroxylation of taurine 50, identified the conserved Fe(II) binding triad of H150, H288, and D152, as well as the α-ketoglutarate binding residues R290 and R309. A surprising difference is observed between FrbJ and TauD in the structure of a lid that is proposed to close over the active site upon substrate binding, as well as the presence of an unusual tunnel that provides a second route into the active site.…”

Section: Chemical Reviewsmentioning

confidence: 99%

Phosphonate Biochemistry

2016

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Organophosphonic acids are unique as natural products in terms of stability and mimicry. The C-P bond that defines these compounds resists hydrolytic cleavage, while the phosphonyl group is a versatile mimic of transition-states, intermediates, and primary metabolites. This versatility may explain why a variety of organisms have extensively explored the use organophosphonic acids as bioactive secondary metabolites. Several of these compounds, such as fosfomycin and bialaphos, figure prominently in human health and agriculture. The enzyme reactions that create these molecules are an interesting mix of chemistry that has been adopted from primary metabolism as well as those with no chemical precedent. Additionally, the phosphonate moiety represents a source of inorganic phosphate to microorganisms that live in environments that lack this nutrient; thus, unusual enzyme reactions have also evolved to cleave the C-P bond. This review is a comprehensive summary of the occurrence and function of organophosphonic acids natural products along with the mechanisms of the enzymes that synthesize and catabolize these molecules.

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“…[24][25][26][27][28][29][30] This feature has also been observed in some Fe/αKG-dependent superfamily enzymes such as AlkB. [31][32][33][34][35] Yu et al proposed the possibility of oxygen diffusion by intra-molecular tunnels based on the original AlkB crystal structure. 34 Subsequently, a computational investigation showed the likelihood of the existence of two O2-transporting tunnels in this enzyme by various computational approaches.…”

Section: Introductionmentioning

confidence: 82%

Computational Investigation of a Series of Small Molecules as Lead Compounds for Lysyl hydroxylase-2 (LH2) Inhibition

Maghsoud

Vázquez-Montelongo

Yang

et al. 2022

Preprint

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The catalytic function of Lysyl hydroxylase-2 (LH2), a member of the Fe(II)/αKG-dependent oxygenase superfamily, is to catalyze the hydroxylation of lysine to hydroxylysine in collagen, resulting in stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs). Reports show that high amounts of LH2 lead to the accumulation of HLCCs, causing fibrosis and specific types of cancer metastasis. Some members of the Fe(II)/αKG-dependent family have also been reported to have intramolecular O2 tunnels, which aid in transporting one of the required co-substrates into the active site. While LH2 can be a promising target to combat these diseases, efficacious inhibitors are still lacking. We have used computational simulations to investigate a series of forty-four small molecules as lead compounds for LH2 inhibition. Tunneling analyses indicate the existence of several intra-molecular tunnels. The lengths of the calculated O2-transporting tunnels in holoenzymes are relatively longer than the apoenzyme suggesting that the ligands may affect the enzyme's structure and possibly block (at least partially) the tunnels. The sequence alignment analysis between LH enzymes from different organisms shows that all the amino acid residues with the highest occurrence rate in the oxygen tunnels are conserved. Our results suggest that the enolate form of diketone compounds establishes stronger interactions with the Fe(II) in the active site. Branching the enolate compounds with functional groups such as phenyl and pyridinyl enhances the interaction with various residues around the active site. Our results provide information about possible leads for further LH2 inhibition design and development.

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Structural analysis of a phosphonate hydroxylase with an access tunnel at the back of the active site

Cited by 6 publications

References 26 publications

Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases

Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases

Phosphonate Biochemistry

Computational Investigation of a Series of Small Molecules as Lead Compounds for Lysyl hydroxylase-2 (LH2) Inhibition

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