## 3 Genetic Organization and Regulation of SM Genes  
The genes responsible for SM synthesis are usually clustered in the fungal genomes sharing the same regulation [58]. Typical SM gene clusters contain a key pathway gene, coding for a PKS, a NRPS, or a terpene cyclase, which is often easily identified by its larger size. They also contain genes for other modifying enzymes frequently belonging to easily recognizable families, e.g., P450 monooxygenases [59], and in some cases genes for permeases involved in their excretion. SM biosynthetic pathways can be controlled by specific regulatory genes [60] frequently belonging to the Zn cluster family and normally included in the corresponding cluster. As a prototypical example, in _F. fujikuroi_ the transcription factor BiK5 is necessary for the synthesis of bikaverin, supported in this case by a second regulatory protein Bik4 [61]. In other cases, regulatory genes are not found in the cluster, as occurs with the gibberellin cluster in the same species [27] or in penicillin and cephalospororus clusters in other fungi [62]. Due to the interest of SM production, much attention has been devoted to its regulatory mechanisms. SM clusters are regulated by a diversity of environmental cues and are controlled by different regulatory proteins, which are frequently involved in more general regulatory networks [63; 64]. External signals controlling SM biosynthesis include the availability of nitrogen or carbon sources, pH, or light, mediated by global regulation systems that act simultaneously on different SM clusters as well as on other metabolic processes [65]. Regulation of SM production by nitrogen is very frequent [66], and different proteins participate in it, among which AreA-like proteins play a pivotal role. Carbon source availability affects many metabolic processes [67], including SM production [68], that usually involve a catabolite repressor of the CreA family. SM regulation by pH is usually controlled by proteins of the PacC family, with examples in different fungi [69]. Another general regulator of special interest is \(\mathrm{LaeA}\)[70], which is associated with light regulation and development control with Velvet proteins forming a complex [71; 72]. It has recently been observed that the main regulator by light in _F. fujikuroi_, WcoA, positively or negatively controls different SM clusters in this fungus [73]. This double positive/negative role on different pathways is frequent in these global regulatory systems, even when responding to the same signal. For example, \(\mathrm{AreA}\) mutation results in derepression of gibberellin biosynthesis in _F. fujikuroi_[74], but repression of fumonisin production in _F. verticillioides_[75]. Examples of mutations on genes affecting fungal SM production--in some cases encoding enzymes, as found for glutamine synthetase in _F. fujikuroi_[76]--have been abundantly described in the literature. SM clusters may be in any chromosomal region, but in many cases they are found in subtelomeric regions [77]. Such locations may be associated with epigenetic silencing in the form of heterochromatin. Supporting this, some regulatory proteins modulate SM production at the level of chromatin structure by histone modifications [78], a conclusion reinforced by the effects of mutations of genes involved in such modifications, such as that for the methyltransferase Kmtt6 in _Fusarium_ sp. [79; 80]. This level of regulation provides a selective advantage to the genomic organization as clusters since it allows the simultaneous inactivation of all the genes of a pathway through heterochromatinization. This is the way through which LaeA acts in the Velvet complex, but other regulatory proteins, such as AreA, also participate in this control mechanism [81].