New insights into the isopenicillin N transport in Penicillium chrysogenum

Fernández-Aguado, Marta; Martı́n, Juan F.; Rodríguez-Castro, Raquel; Garcı́a-Estrada, Carlos; Albillos, Silvia M.; Teijeira, Fernando; Ullán, Ricardo V.

doi:10.1016/j.ymben.2014.01.004

Cited by 30 publications

(32 citation statements)

References 55 publications

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“…In addition to the enzymes of the penicillin biosynthetic pathway, two predicted peroxisome membrane associated proteins have been implicated in penicillin G synthesis in P. chrysogenum (Figure 1A ). PaaT protein has been linked to phenylacetic acid transport and PenM protein associated with IPN uptake at the peroxisome membrane (Fernández-Aguado et al, 2013b , 2014 ). Both proteins were DS-Red labeled and shown to be peroxisomal by co-localization with GFP-SKL constructs.…”

Section: Peroxisomesmentioning

confidence: 99%

Cellular compartmentalization of secondary metabolism

2015

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Fungal secondary metabolism is often considered apart from the essential housekeeping functions of the cell. However, there are clear links between fundamental cellular metabolism and the biochemical pathways leading to secondary metabolite synthesis. Besides utilizing key biochemical precursors shared with the most essential processes of the cell (e.g., amino acids, acetyl CoA, NADPH), enzymes for secondary metabolite synthesis are compartmentalized at conserved subcellular sites that position pathway enzymes to use these common biochemical precursors. Co-compartmentalization of secondary metabolism pathway enzymes also may function to channel precursors, promote pathway efficiency and sequester pathway intermediates and products from the rest of the cell. In this review we discuss the compartmentalization of three well-studied fungal secondary metabolite biosynthetic pathways for penicillin G, aflatoxin and deoxynivalenol, and summarize evidence used to infer subcellular localization. We also discuss how these metabolites potentially are trafficked within the cell and may be exported.

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Section: Peroxisomesmentioning

confidence: 99%

Cellular compartmentalization of secondary metabolism

2015

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“…Surprisingly, this mutant produced normal amounts of benzylpenicillin when 6-APA was supplied extracellularly to the cells. [29]. The formation in vivo of benzylpenicillin in cultures supplemented with 6-APA was linearly dependent on the amount of 6-APA supplied to the cells.…”

Section: Transport Of Ipn Into Peroxisomesmentioning

confidence: 96%

“…Due to the localization of the early biosynthetic enzymes in the cytosol, in contrast to the peroxisomal residence of the phenylacetyl-CoA ligase and IAT, the progress of reactions in the penicillin biosynthesis route requires transport of the side chain precursors and cofactors needed for the final steps of penicillin biosynthesis. There is information on the transport into peroxisomes of fatty acids and cofactors [7,74] but, until recently, there was very little information on the import of small aromatic or heterocyclic pathway intermediates into peroxisomes [28,29].…”

Section: Compartmentalization Of the Last Two Enzymes Of Penicillin Bmentioning

confidence: 99%

“…A major facilitator superfamily (MFS) transporter was found in P. chrysogenum, that is similar to a membrane protein located in microbodies of A. chrysogenum [29]. The P. chrysogenum protein named penM (for microbodies) is encoded by Pc21g09220 gene.…”

Section: Transport Of Ipn Into Peroxisomesmentioning

confidence: 99%

“…The P. chrysogenum protein named penM (for microbodies) is encoded by Pc21g09220 gene. PenM has 12 transmembrane spanning domains (MSD) and a size of 508 amino acids [29].…”

Section: Transport Of Ipn Into Peroxisomesmentioning

confidence: 99%

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Transport systems, intracellular traffic of intermediates and secretion of β-lactam antibiotics in fungi

Martı́n

2020

Fungal Biol Biotechnol

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Fungal secondary metabolites are synthesized by complex biosynthetic pathways catalized by enzymes located in different subcellular compartments, thus requiring traffic of precursors and intermediates between them. The β-lactam antibiotics penicillin and cephalosporin C serve as an excellent model to understand the molecular mechanisms that control the subcellular localization of secondary metabolites biosynthetic enzymes. Optimal functioning of the β-lactam biosynthetic enzymes relies on a sophisticated temporal and spatial organization of the enzymes, the intermediates and the final products. The first and second enzymes of the penicillin pathway, ACV synthetase and IPN synthase, in Penicillium chrysogenum and Aspergillus nidulans are cytosolic. In contrast, the last two enzymes of the penicillin pathway, phenylacetyl-CoA ligase and isopenicillin N acyltransferase, are located in peroxisomes working as a tandem at their optimal pH that coincides with the peroxisomes pH. Two MFS transporters, PenM and PaaT have been found to be involved in the import of the intermediates isopenicillin N and phenylacetic acid, respectively, into peroxisomes. Similar compartmentalization of intermediates occurs in Acremonium chrysogenum; two enzymes isopenicillin N-CoA ligase and isopenicillin N-CoA epimerase, that catalyse the conversion of isopenicillin N in penicillin N, are located in peroxisomes. Two genes encoding MFS transporters, cefP and cefM, are located in the early cephalosporin gene cluster. These transporters have been localized in peroxisomes by confocal fluorescence microscopy. A third gene of A. chrysogenum, cefT, encodes an MFS protein, located in the cell membrane involved in the secretion of cephalosporin C, although cefT-disrupted mutants are still able to export cephalosporin by redundant transporters. The secretion of penicillin from peroxisomes to the extracellular medium is still unclear. Attempts have been made to identify a gene encoding the penicillin secretion protein among the 48 ABC-transporters of P. chrysogenum. The highly efficient secretion system that exports penicillin against a concentration gradient may involve active penicillin extrusion systems mediated by vesicles that fuse to the cell membrane. However, there is no correlation of pexophagy with penicillin or cephalosporin formation since inactivation of pexophagy leads to increased penicillin or cephalosporin biosynthesis due to preservation of peroxisomes. The penicillin biosynthesis finding shows that in order to increase biosynthesis of novel secondary metabolites it is essential to adequately target enzymes to organelles.

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Bacterial Proteases as Targets to Control Bacterial Growth

Ullán

Barreiro

2016

New Weapons to Control Bacterial Growth

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New insights into the isopenicillin N transport in Penicillium chrysogenum

Cited by 30 publications

References 55 publications

Cellular compartmentalization of secondary metabolism

Cellular compartmentalization of secondary metabolism

Transport systems, intracellular traffic of intermediates and secretion of β-lactam antibiotics in fungi

Bacterial Proteases as Targets to Control Bacterial Growth

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