Role of peroxisomes in the biosynthesis and secretion of β-lactams and other secondary metabolites

Abstract

Peroxisomes are eukaryotic organelles surrounded by a single bilayer membrane, containing a variety of proteins depending on the organism; they mainly perform degradation reactions of toxic metabolites (detoxification), catabolism of linear and branched-chain fatty acids, and removal of H(2)O(2) (formed in some oxidative processes) by catalase. Proteins named peroxins are involved in recruiting, transporting, and introducing the peroxisomal matrix proteins into the peroxisomes. The matrix proteins contain the peroxisomal targeting signals PTS1 and/or PTS2 that are recognized by the peroxins Pex5 and Pex7, respectively. Initial evidence indicated that the penicillin biosynthetic enzyme isopenicillin N acyltransferase (IAT) of Penicillium chrysogenum is located inside peroxisomes. There is now solid evidence (based on electron microscopy and/or biochemical data) confirming that IAT and the phenylacetic acid- and fatty acid-activating enzymes are also located in peroxisomes. Similarly, the Acremonium chrysogenum CefD1 and CefD2 proteins that perform the central reactions (activation and epimerization of isopenicillin N) of the cephalosporin pathway are targeted to peroxisomes. Growing evidence supports the conclusion that some enzymes involved in the biosynthesis of mycotoxins (e.g., AK-toxin), and the biosynthesis of signaling molecules in plants (e.g., jasmonic acid or auxins) occur in peroxisomes. The high concentration of substrates (in many cases toxic to the cytoplasm) and enzymes inside the peroxisomes allows efficient synthesis of metabolites with interesting biological or pharmacological activities. This compartmentalization poses additional challenges to the cell due to the need to import the substrates into the peroxisomes and to export the final products; the transporters involved in these processes are still very poorly known. This article focuses on new aspects of the metabolic processes occurring in peroxisomes, namely the degradation and detoxification processes that lead to the biosynthesis and secretion of secondary metabolites.

The inducers 1,3-diaminopropane and spermidine cause the reprogramming of metabolism in Penicillium chrysogenum, leading to multiple vesicles and penicillin overproduction

“…Conidia from one Petri dish were collected and inoculated into a flask with 100 ml of defined medium PMMY. It contains (g/l): NaNO 3 …”

“…The biosynthesis of penicillin in Penicillium chrysogenum is an excellent model to study the molecular mechanisms of biosynthesis, control of gene expression and secretion of secondary metabolites in fungi [1][2][3] due to the excellent knowledge accumulated on the biosynthesis [4,5] and molecular genetics of this β-lactam compound [3,6,7]. The penicillin biosynthetic pathway (Fig.…”

“…Next, the acyl-CoA: 6-APA acyltransferase activity introduces the new activated acyl side chain. Activation of the precursor acyl molecules as CoA thioesters (phenylacetyl-CoA from phenylacetate in the case of benzylpenicillin) is a prerequisite for the incorporation of acyl side chains during the biosynthesis of hydrophobic penicillins and peroxisomal acyl-CoA ligases are in charge of such activation [2,3].…”

“…The penicillin biosynthetic pathway (Fig. 1) has been extensively reviewed [2][3][4][5][6][7]. Penicillin biosynthesis starts in the cytosol with the formation of the tripeptide δ-L-(α-aminoadipyl)-L-cysteinyl-D-valine (ACV) after the non-ribosomal condensation of L-α-aminoadipic acid, L-cysteine and L-valine.…”

The autophagy-related gene Acatg1 is involved in conidiation and cephalosporin production in Acremonium chrysogenum

“…So far, cephalosporin has been widely used in treatment of bacterial infectious diseases and is one of the major biotechnological products (Poggeler et al, 2008). In recent years, considerable progress has been made in understanding cephalosporin biosynthesis in A. chrysogenum (Dreyer et al, 2007;Long et al, 2013;Lopez-Calleja et al, 2012;Martin et al, 2010Martin et al, , 2012Schmitt et al, 2004aSchmitt et al, , 2004bSchmitt et al, , 2004cTeijeira et al, 2009). Cephalosporin production is extensively affected by different factors such as carbon and nitrogen sources, ambient pH and oxidative stress, indicating cephalosporin biosynthesis is highly controlled (Brakhage et al, 2009).…”