Biochemical and Structural Insights into the Aminotransferase CrmG in Caerulomycin Biosynthesis

Zhu, Yiguang; Xu, Jinxin; Mei, Xiangui; Zhan, Feng; Zhang, Liping; Zhang, Qingbo; Zhang, Guangtao; Zhu, Weiming; Liu, Jinsong

doi:10.1021/acschembio.5b00984

Cited by 26 publications

(35 citation statements)

References 56 publications

(116 reference statements)

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“…However, the mutations that cause these shifts toward the GTP-bound form are distinct from those that activate RAS proteins, with the exception of one mutation corresponding to Q61 in RAS proteins (Q79 in Rit1). The lack of frequent mutations at codon 12, 13, and 61 equivalents is thought to be because substitutions in these codons create splice sites or termination codons (Zhu et al, 2016). Rit proteins activate RAF kinase, RalGDS, PI3Kα, and PI3Kγ (Rodriguez-Viciana et al, 2004).…”

Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,372

1,350

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RAS proteins are binary switches, cycling between ON and OFF states during signal transduction. These switches are normally tightly controlled, but in RAS-related diseases, such as cancer, RASopathies, and many psychiatric disorders, mutations in the RAS genes or their regulators render RAS proteins persistently active. The structural basis of the switch and many of the pathways that RAS controls are well known, but the precise mechanisms by which RAS proteins function are less clear. All RAS biology occurs in membranes: a precise understanding of RAS’ interaction with membranes is essential to understand RAS action and to intervene in RAS-driven diseases.

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Section: Ras and Human Diseasementioning

confidence: 99%

RAS Proteins and Their Regulators in Human Disease

Simanshu

Nissley

McCormick

2017

Cell

1,372

1,350

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“…Heterologous expression of this gene cluster in S. coelicolor resulted in production of 38 , confirming its link to caerulomycin biosynthesis. 148 The most likely candidate for N -oxygenation in this pathway was CrmH, a predicted two-component flavin monooxgenase with 30% sequence similarity to the isobutylamine hydroxylase VlmH in valanimycin biosynthesis (Section 3.1.1) 134,149 Gene inactivation of crmH resulted in accumulation of the corresponding amine ( 42 , Scheme 5) in culture extracts, suggesting that CrmH catalyzed oxime formation via N -oxidation of an amine precursor ( 42 → 38 ). 134 …”

Section: N–o Bond Forming Enzymesmentioning

confidence: 99%

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

et al. 2017

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Natural products that contain functional groups with heteroatom-heteroatom linkages (X–X, where X = N, O, S, and P) are a small yet intriguing group of metabolites. The reactivity and diversity of these structural motifs has captured the interest of synthetic and biological chemists alike. Functional groups containing X–X bonds are found in all major classes of natural products and often impart significant biological activity. This review presents our current understanding of the biosynthetic logic and enzymatic chemistry involved in the construction of X–X bond containing functional groups within natural products. Elucidating and characterizing biosynthetic pathways that generate X–X bonds could both provide tools for biocatalysis and synthetic biology, as well as guide efforts to uncover new natural products containing these structural features.

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“…2). The cam contains 20 ORFs including essential dipyridine ring biosynthetic genes and backbone post-modi cation genes [23,26,[28][29][30] (Fig. 2 and Table S4), which indicates that Actinoalloteichus sp.…”

Section: Genomic Analysis Of the Crm A Biosynthetic Potential In Actimentioning

confidence: 99%

“…The biosynthesis of this marine drug lead is initiated by the formation of a core 2, 2'-dipyridine skeleton, which is catalyzed by a unique hybrid polyketide-nonribosomal peptide (PKS-NRPS) assembly line [22][23][24][25][26]. Then, the 2, 2'-dipyridine skeleton is nally converted into the CRM A by a series of post-modi cation reactions, including aminohydrolysis, oxime formation and methylation [23,[27][28][29][30]. CRM A can induce the generation of regulatory T cells to avoid T cell responses and change the function of B cells, which signi cantly inhibits the Mixed Lymphocyte Reaction (MLR) [31,32].…”

Section: Introductionmentioning

confidence: 99%

Activation and enhancement of Caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies

Xie

Chen

Wang

et al. 2020

Preprint

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Backgrounds: Activation of silent biosynthetic gene clusters (BGCs) in marine-derived actinomycete strains is a feasible strategy to discover bioactive natural products. Actinoalloteichus sp. AHMU CJ021, isolated from the seashore, was shown to contain an intact but silent caerulomycin A (CRM A) BGC- cam in its genome. Thus, a genome mining work was preformed to activate the strain’s production of CRM A, an immunosuppressive drug lead with diverse bioactivities.Results: To well activate the expression of cam , ribosome engineering was adopted to treat the wild type Actinoalloteichus sp. AHMU CJ021. The initial mutant strain XC-11G with gentamycin resistance and CRM A production titer of 42.51 ± 4.22 mg/L was selected from all generated mutant strains by gene expression comparison of the essential biosynthetic gene-camE. The titer of CRM A production was then improved by two strain breeding methods via UV mutagenesis and cofactor engineering-directed increase of intracellular riboflavin, which finally generated the optimal mutant strain XC-11GUR with a CRM A production titer of 113.91 ± 7.58 mg/L. Subsequently, this titer of strain XC-11GUR was improved to 618.61 ± 16.29 mg/L through medium optimization together with further adjustment derived from response surface methodology. In terms of this 14.6 folds increase in the titer of CRM A compared to the initial value, strain XC-GUR could be a well alternative strain for CRM A development.Conclusions: Our results have constructed an ideal CRM A producer. More importantly, our efforts also have demonstrated the effectiveness of abovementioned combinatorial strategies, which is applicable to the genome mining of bioactive natural products from abundant actinomycetes strains.

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Biochemical and Structural Insights into the Aminotransferase CrmG in Caerulomycin Biosynthesis

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Cited by 26 publications

References 56 publications

RAS Proteins and Their Regulators in Human Disease

RAS Proteins and Their Regulators in Human Disease

Heteroatom–Heteroatom Bond Formation in Natural Product Biosynthesis

Activation and enhancement of Caerulomycin A biosynthesis in marine-derived Actinoalloteichus sp. AHMU CJ021 by combinatorial genome mining strategies

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