Structural enzymology of iterative type I polyketide synthases: various routes to catalytic programming

Wang, Jialiang; Deng, Zixin; Ji, Liang; Wang, Zhijun

doi:10.1039/d3np00015j

Cited by 13 publications

(4 citation statements)

References 103 publications

(168 reference statements)

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“…1A and S1). (ii) The iterative PKSs, which are monomodular systems, synthesize PKs via multiple cycles of chain elongation and processing carried out by the same module [11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds

Grininger,

Buyachuihan,

Reiners

et al. 2024

Preprint

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Modular polyketide synthases (PKSs) play a vital role in the biosynthesis of complex natural products with pharmaceutically relevant properties. Their modular architecture makes them an attractive target for engineering to produce platform chemicals and drugs. In this study, we demonstrate that the promiscuous malonyl/acetyl-transferase domain (MAT) from murine fatty acid synthase serves as a highly versatile tool for the production of polyketide analogs. We evaluate the relevance of the MAT domain using three modular PKSs; the short trimodular venemycin synthase (VEMS), as well as modules of the PKSs deoxyerythronolide B synthase (DEBS) and pikromycin synthase (PIKS) responsible for the production of the antibiotic precursors erythromycin and pikromycin. To assess the performance of the MAT-swapped PKSs, we analyze the protein quality and run engineered polyketide syntheses in vitro. Our experiments include the chemoenzymatic synthesis of fluorinated macrolactones. Our study showcases MAT-based reprogramming of polyketide biosynthesis as a facile option for the regioselective editing of polyketide scaffolds.

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“…1A and S1). (ii) The iterative PKSs, which are monomodular systems, synthesize PKs via multiple cycles of chain elongation and processing carried out by the same module [11][12][13][14] .…”

Section: Introductionmentioning

confidence: 99%

The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds

Grininger,

Buyachuihan,

Reiners

et al. 2024

Preprint

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“…Polyketides represent a diverse group of natural products and have profoundly impacted human health through the development of therapeutics, including anti-infectives like erythromycin and amphotericin B; immunosuppressants such as tacrolimus and rapamycin; and lipid-lowering agents with lovastatin being a primary example. The central enzymes for polyketide biosynthesis are polyketide synthases (PKSs), which are further classified into types I, II, and III and contribute to the generation of a diverse array of molecular architectures.…”

Section: Introductionmentioning

confidence: 99%

Structural and Computational Insights into the Noncanonical Aromatization in Fungal Polyketide Biosynthesis

Wang,

Peng,

Chen

et al. 2024

ACS Catal.

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Aromatic polyketides, with their diverse structures and biological activities, have attracted significant scientific interest. Aromatization reactions are typically performed by aromatases and cyclases associated with bacterial type II polyketide synthases (PKSs) or product template and Claisen cyclase domains found in fungal type I nonreducing PKSs. Intriguingly, our recent study discovered a noncanonical aromatization mechanism involving a cupin domain-containing enzyme, StrC, in fungal alkyl salicylaldehyde derivative biosynthesis. Nevertheless, the catalytic function of StrC largely remained enigmatic. In this study, an indepth in vitro characterization of StrC was performed to gain a better understanding of the reaction mechanism for aromatization. In addition, the X-ray crystal structure of StrC in the complex with a substrate analogue was obtained to elucidate the unique active site. Subsequent mutational experiments identified important amino acid residues for aromatase activity. Furthermore, a quantum mechanics study provided a plausible reaction mechanism for aromatization and highlighted the vital role of StrC in the biosynthetic process. Thus, our study unveils an unknown paradigm for aromatization in polyketide biosynthesis.

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“…In type I PKSs, modules can be composed of different sets of domains. These modules can be used either in iteration (iterative PKSs, extensively reviewed elsewhere [4] ), similar to FASs, or sequentially (modular PKSs, extensively reviewed elsewhere [5] ) with multiple modules of varying domain compositions, resulting in a wide range of structurally diverse PK products. [1,6] Modular PKSs perform vectorial synthesis by using several modules that are aligned sequentially.…”

Section: Introductionmentioning

confidence: 99%

How Acyl Carrier Proteins (ACPs) Direct Fatty Acid and Polyketide Biosynthesis

Buyachuihan,

Stegemann,

Grininger

2023

Angew Chem Int Ed

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Megasynthases, such as type I fatty acid and polyketide synthases (FASs and PKSs), are multienzyme complexes responsible for producing primary metabolites and complex natural products. Fatty acids (FAs) and polyketides (PKs) are built by assembling and modifying small acyl moieties in a stepwise manner. A central aspect of FA and PK biosynthesis involves the shuttling of substrates between the domains of the multienzyme complex. This essential process is mediated by small acyl carrier proteins (ACPs). The ACPs must navigate to the different catalytic domains within the multienzyme complex in a particular order to guarantee the fidelity of the biosynthesis pathway. However, the precise mechanisms underlying ACP‐mediated substrate shuttling, particularly the factors contributing to the programming of the ACP movement, still need to be fully understood. This review illustrates the current understanding of substrate shuttling, including concepts of conformational and specificity control, and proposes a confined ACP movement within type I megasynthases.

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Structural enzymology of iterative type I polyketide synthases: various routes to catalytic programming

Abstract: This article provides a comprehensive overview of the structural enzymology of type I iPKSs, focusing on the individual domain structures, catalytic mechanisms and the representative programming activities that each domain contributes.

Cited by 13 publications

References 103 publications

The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds

The malonyl/acetyl-transferase from murine fatty acid synthase is a promiscuous engineering tool for editing polyketide scaffolds

Structural and Computational Insights into the Noncanonical Aromatization in Fungal Polyketide Biosynthesis

How Acyl Carrier Proteins (ACPs) Direct Fatty Acid and Polyketide Biosynthesis

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