Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes

Lilla, Edward A.; Yokoyama, Kenichi

doi:10.1038/nchembio.2187

Cited by 47 publications

(70 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An essentially identical observation was made for NikJ, the PolH homolog in the biosynthesis of nikkomycins 35 . When the two enzymes were characterized by steady-state kinetic analysis, their catalytic efficiencies were comparable to that of PolA/NikO, indicating the physiological relevance of the reconstituted activity 35 . The Chen and Xiao groups later reported the identical function for PolH 36 , in which they prepared polH gene knockout strain of the polyoxin producer, S. cacaoi , and demonstrated that the polH gene is essential for polyoxin biosynthesis, and the mutant strain accumulated 5′-enolpyruvyl uridine, a shunt metabolite presumably derived from EP-UMP.…”

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesissupporting

confidence: 66%

“…6B), demonstrating that PolH alone is sufficient to convert EP-UMP into OAP 35 . An essentially identical observation was made for NikJ, the PolH homolog in the biosynthesis of nikkomycins 35 . When the two enzymes were characterized by steady-state kinetic analysis, their catalytic efficiencies were comparable to that of PolA/NikO, indicating the physiological relevance of the reconstituted activity 35 .…”

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesismentioning

confidence: 97%

“…Isolation and structural characterization of the product identified it as octosyl acid 5′-phosphate (OAP, Fig. 6B), demonstrating that PolH alone is sufficient to convert EP-UMP into OAP 35 . An essentially identical observation was made for NikJ, the PolH homolog in the biosynthesis of nikkomycins 35 .…”

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesismentioning

confidence: 99%

See 2 more Smart Citations

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

Yokoyama

2017

Biochemistry

Self Cite

View full text Add to dashboard Cite

The radical SAM (S-adenosyl-L-methionine) superfamily is one of the largest group of enzymes with >113,000 annotated sequences1. Members of this superfamily catalyze the reductive cleavage of SAM using an oxygen sensitive 4Fe-4S cluster to transiently generate 5′-deoxyadenosyl radical (5′-dA•) that is subsequently used to initiate diverse free radical-mediated reactions. Because of the unique reactivity of free radicals, radical SAM enzymes frequently catalyze chemically challenging reactions critical for the biosynthesis of unique structures of cofactors and natural products. In this perspective, I will discuss the impact of characterizing novel functions in radical SAM enzymes on our understanding of biosynthetic pathways and use two recent examples from my own group with particular emphasis on two radical SAM enzymes responsible for carbon skeleton formation during the biosynthesis of a cofactor and natural products.

show abstract

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesissupporting

confidence: 66%

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesismentioning

confidence: 97%

Section: Antifungal Peptidyl Nucleoside Natural Product Biosynthesismentioning

confidence: 99%

See 1 more Smart Citation

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

Yokoyama

2017

Biochemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Its ability to potentiate the antifungal activity of echinocandins makes nikkomycin Z plus an echinochandin an ideal broad-spectrum drug combination to attack the fungal cell wall in both yeasts and moulds. Furthermore, new chemistry studies of the peptidyl nucleoside antibiotics, which includes nikkomycins and polyoxins, may enable further development of this class of compounds 83 .…”

Section: New Agents In Developmentmentioning

confidence: 99%

The antifungal pipeline: a reality check

Perfect

2017

Nat Rev Drug Discov

641

575

View full text Add to dashboard Cite

Invasive fungal infections continue to appear in record numbers as the immunocompromised population of the world increases, owing partially to the increased number of individuals who are infected with HIV and partially to the successful treatment of serious underlying diseases. The effectiveness of current antifungal therapies — polyenes, flucytosine, azoles and echinocandins (as monotherapies or in combinations for prophylaxis, or as empiric, pre-emptive or specific therapies) — in the management of these infections has plateaued. Although these drugs are clinically useful, they have several limitations, such as off-target toxicity, and drug-resistant fungi are now emerging. New antifungals are therefore needed. In this Review, I discuss the robust and dynamic antifungal pipeline, including results from preclinical academic efforts through to pharmaceutical industry products, and describe the targets, strategies, compounds and potential outcomes.

show abstract

“…However, in these cases, there is no re-aromatization through oxidation. Instead, the radical is quenched through reduction (24,25).…”

Section: Carbon-carbon Bond Creation: Pqqe Strb and Mftcmentioning

confidence: 99%

At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology

Latham

Barr

Klinman

2017

Journal of Biological Chemistry

View full text Add to dashboard Cite

Radical S-adenosylmethionine (RS) enzymology has emerged as a major biochemical strategy for the homolytic cleavage of unactivated C-H bonds. At the same time, the post-translational modification of ribosomally synthesized peptides is a rapidly expanding area of investigation. We discuss the functional cross-section of these two disciplines, highlighting the recently uncovered importance of protein-protein interactions, especially between the peptide substrate and its chaperone, which functions either as a stand-alone protein or as an N-terminal fusion to the respective RS enzyme. The need for further work on this class of enzymes is emphasized, given the poorly understood roles performed by multiple, auxiliary iron-sulfur clusters and the paucity of protein X-ray structural data.Modern biochemistry has seen the exponential growth of two exciting areas of research that focus individually on the post-translational modification of ribosomally synthesized and post-translationally modified peptides (RiPPs) 2 (1) and on the structure and mechanism of free radical conversions catalyzed by radical S-adenosylmethionine (RS) enzymes (2, 3). These separate fields have recently converged within a growing family of enzymes that bring about free radical-based, post-translational modifications on ribosomally produced peptide substrates. RS enzymes function by cleavage of a [4Fe-4S] clusterbound S-adenosylmethionine to form methionine and a deoxyadenosyl radical. This radical then initiates the reaction by abstracting a hydrogen atom from the substrate. The [4Fe-4S] cluster that accomplishes this reaction has a characteristic CX 3 CXC motif, with each of the cysteines coordinated to a single iron, leaving an open coordination sphere where SAM binds and is cleaved. A subset of RS enzymes belongs to a family that contains an additional conserved structural motif annotated as a SPASM domain and referred to as RS-SPASM proteins. Although the exact function of the SPASM domain is unknown, it has been shown that it houses generally two additional iron-sulfur clusters that are critical in RS-SPASM chemistry. Using the perspective of the pathway for production of the bacterial cofactor pyrroloquinoline quinone (PQQ), we compare and highlight some of the unique properties among these RS-SPASM-dependent RiPP systems. Bioinformatics analyses suggest that the family members will extend far beyond the examples presented herein.

show abstract

Carbon extension in peptidylnucleoside biosynthesis by radical SAM enzymes

Cited by 47 publications

References 27 publications

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

Radical Breakthroughs in Natural Product and Cofactor Biosynthesis

The antifungal pipeline: a reality check

At the confluence of ribosomally synthesized peptide modification and radical S-adenosylmethionine (SAM) enzymology

Contact Info

Product

Resources

About