## 3 _Apergillus_ Is a Microbial Chassis for Natural Product Synthesis
### A. oryzae Is a Chassis for Natural Product Production
#### 3.1.2 The Production of Terpenoids in _A. oryzae_  
Terpenoids, the largest family and the most diverse group of natural products with over 90,000 structures reported, are derived from C\({}_{5}\) of isopentenyl diphosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMAPP). They are typically formed by terpene cyclases and further modified through oxidation, hydroxylation, glycosylation, or other enzymatic reactions [70]. According to the carbon numbers of the terpenoid molecule, they are categorized as monoterpencids (C10), sesquiterpenoids (C15), triterpen (C20), sesterterpenoids (C25), or triterpen (C30) [71]. Due to their beneficial therapeutic properties including anti-cancer, anti-oxidation, antibacterial, antiviral, antimalarial, and potent anti-inflammatory activities, terpenoids are significant sources of natural product drugs, including menthol (monoterpenes), the well-known antimalarial drug artemisinin (sesquiterpenes), vitamin A, the anti-cancer drug paclitaxel (diterpenes), ginseng (triterpenoids), the cardiovascular drug tanshinone and so on [72; 73; 74; 75; 76]. In nature, terpenoid biosynthesis mainly occurs through two distinct pathways: the 2-C-methyl-D-erythnitol-4-phosphate (MEP) pathway, predominantly in bacteria and plant plastids, and the mexionate (MVA) pathway, primarily in eukaryotes and archaea [77]. As shown in Figure 2, _A. oryzae_ possesses almost all precursor compounds for terpenoid synthesis, including IPP, DMAPP, geranyl pyrophosphate (GPP), farnesyl pyrophosphate (FPP), and geranylgeranyl pyrophosphate (GGPP) generated through the MVA pathway [78]. Moreover, _A. oryzae_ exhibits robust protein secretion machinery and a superior post-translational modification capacity, enabling the precise recognition and splicing of introns. These attributes allow for the efficient heterologous expression of nearly all terpenoid cyclases in this fungal system [79]. Therefore, _A. oryzae_ is an excellent heterologous expression chassis for terpenoids, particularly suitable for expressing fungal or plant-derived terpenoid biosynthetic gene(s)/clusters [80]. In recent years, _A. oryzae_ has been widely applied in research on terpenoid biosynthesis, genomic mining, and synthetic biology. Here, we systematically review recent advances in terpenoid production using _A. oryzae_ as a heterologous host, organized according to terpenoid classification systems. Table 1 presents the representative terpenoid's heterologously produced in _A. oryzae_. Sesquiterpencids  
Sesquiterpencids are ubiquitously distributed in the tissues of plants, marine organisms, microorganisms, and insects. Although they comprise a conserved C\({}_{15}\) carbon skeleton, sesquiterpenoids exhibit remarkable skeletal diversity through multienzymatic secondary metabolic processes, generating over 180 skeletal frameworks and complex derivatives [81; 82]. Thus, sesquiterpenoids represent one of the largest and most structurally diverse classes of terpenoids in terms of both quantitative abundance and chemical complexity. [PERSON] et al. identified a novel type of sesquiterpenoid synthase gene cluster from _Botrytia cinerea_ and achieved the biosynthesis of abscisic acid using _A. oryzae_ as a heterologous expression host to biosynthesisize a sesquiterpene alcohol with a novel skeleton, trichobrasilenol [84]. Moreover, [PERSON] et al. heterologously expressed braA (terpene cyclase), braB (N-acetylglucosamineaminidaseidase), and braC (P450 oxidase) from _Annulhydroxylon truncatum_ in _A. oryzae_, resulting in the biosynthesis of novel compounds brasilane A, brasilane D, and brasilane E [85]. Furthermore, [PERSON] et al. applied the hot-spot knock-in method and incorporated 13 malleolide biosynthetic genes into _A. oryzae_ through stepwise reconstitution. Consequently, they successfully isolated 1\(\alpha\)-hydroxymelleolide, a representative sesquiterpenoid and natural malleolide derivative, and elucidated its biosynthetic pathway [86]. Additionally, using _A. oryzae_ as a heterologous expression system, [PERSON] et al.