Great progress has been made in understanding the regulation of expression of genes involved in secondary metabolism. because this mycotoxin is highly toxic mutagenic and carcinogenic in humans and animals. Using aflatoxin synthesis to illustrate key concepts this review focuses on the mechanisms by which sub-cellular compartmentalization and intra-cellular molecular traffic contribute to the initiation and completion of secondary metabolism within the cell. We discuss the recent discovery of aflatoxisomes specialized trafficking vesicles that participate in the compartmentalization of aflatoxin synthesis and export of the toxin to the cell exterior; this work provides a new and clearer understanding of how cells integrate secondary metabolism into basic cellular metabolism via the intracellular trafficking machinery. Introduction Secondary metabolism Secondary metabolites are an extremely diverse group of natural products synthesized by plants fungi bacteria algae and animals (Hoffmeister & Keller 2007 Keller (Chanda results in re-direction of carbon flow within fungal cells (Roze that encodes a global regulator of secondary metabolism and development (ΔΔgrown in liquid shake culture (under conditions where the block in secondary metabolism is observed but no fungal development occurs) produced significantly higher levels of ethanol and volatile compounds derived from branched chain amino acids in comparison to the wild type. Second an evolutionary link between secondary and primary metabolism is supported by studies that suggest that secondary metabolic pathways “borrow” enzymes from primary metabolism and establish novel cellular functions for these existing enzymes via random mutation (Firn & Ki 20227 Jones 2009 Greenhagen a nuclear acetyl-CoA synthetase that generates acetyl-CoA from acetate is a rate limiting step for histone acetylation (Takahashi all three strains carry a defective and accumulate non-physiologically high levels of NA. Substrates for amino acid- derived secondary Ki 20227 metabolites In. spp synthesize a variety of polyketide antibiotics using complex starter units including isobutyryl-CoA isovaleryl-CoA and 2-methylbutyryl-CoA; the latter are derived from catabolism of the branched chain amino acids valine leucine and isoleucine (Denoya serve as important illustrations for this concept. Plant secondary metabolites Alkaloids Alkaloids Ki 20227 are low molecular weight compounds characterized by a heterocyclic backbone containing nitrogen; alkaloid biosynthesis has been reviewed extensively (Blunt (accumulation is mediated by an ABC transporter and an H+/berberine antiporter) (Otani (Sirikantaramas L.). Among the approximately 70 cannabinoids characterized to date delta (1)-tetrahydrocannabinol (THC) is the best -known psychoactive compound. THC biosynthesis occurs in glandular trichomes and begins Rabbit polyclonal to RAD17. with condensation of geranyl pyrophosphate with olivetolic acid to produce cannabigerolic acid (CBGA); the reaction is catalyzed by an enzyme called geranylpyrophosphate:olivatolate geranyltransferase. CBGA Ki 20227 then undergoes oxidative cyclization to generate tetrahydrocannabinolic acid (THCA) in the presence of THCA synthase. THCA is then transformed into THC by non-enzymatic decarboxylation. Sub-cellular localization studies using RT-PCR and enzymatic activity analyses demonstrate that THCA synthase is expressed in the secretory cells of glandular trichomes and then is translocated into the Ki 20227 secretory cavity where the end product THCA accumulates (Sirikantaramas mycelia grown in submerged culture. Later we used a novel time-fractionated fungal colony technique Western blot analysis and immunofluorescence microscopy to detect Nor-1 Ver-1 and OmtA in grown under aflatoxin inducing conditions on a solid growth medium (YES). These three enzymes were not present between 0 and 24 h after inoculation but were detected in large quantity in 24 to 48 Ki 20227 h old mycelium (Lee mycelia grown in slide culture under aflatoxin-inducing conditions; the fusions were not detected under conditions that restricted aflatoxin biosynthesis. β-Lactam antibiotics The fungal β-lactam antibiotics penicillin G produced.