br Discussion br Acknowledgments Writing of this review and

Discussion
Acknowledgments Writing of this review and collection of data from our laboratories that are presented were supported by a grant from the Belgian Science Policy (BELSPO) SSTC Interuniversity Attraction Poles Plastoscine P7/17 to AVDL and JB, multiple grants from the Fund for Scientific Research Flanders (FWO): grant agreements G030213N, G044311N to AVDL, personal PhD fellowships to Lisbeth Van Ruijssevelt, Jasmien Orije, Tiny Boumans (AVDL promotor), personal Postdoc fellowships to Vincent Van Meir, Geert de Groof, Elisabeth Jonckers (AVDL promotor), and a grant from the Hercules Stichting/Foundation [(middel)zware onderzoeksinfrastructuurprojecten] Pharmascan 70/16 USR (grant agreement no. AUHA/012) to AVDL.
Introduction Cytochrome P450 (CYP) enzymes are pivotal for biological homeostasis. In fact, most drugs target this cluster of membrane-bound enzymes. A common feature of these enzymes are an iron-containing porphyrin group (Fe2+-containing heme) at the active site [1]. The porphyrin serves as prosthetic group of critical biomolecules as cytochromes, hemoglobins, myoglobins, catalases, peroxidases, chlorophylls, among others [1]. Hence, they are essential for catalysis, electron transport, and as drug targets [1]. Aromatase is a CYP enzyme, a monooxygenase coded by the gene CYP19 located in chromosome 15q21 [2], [3]. It converts androgens (C19) to estrogens (C18) by demethylation [4]. As an estrogen biosynthetic enzyme, aromatase is extremely critical. Exhaustive range of physiological functions such as glucose homeostasis, lipid homeostasis, ipa chemical function, follicular growth, bone mineralization, epiphyseal closure, and coordination of the ovulatory process rely on it [5]. Its expression and activity varies in different parts of the body. It is found highly active near gonads, adipose tissues, skin, bone, brain, adrenal gland, liver, placenta, breasts, hair follicles, and it is implicated in tumorigenesis [6]. Gender-specific expression of this enzyme is evident. In fact, higher level of this enzyme along with lower levels of 5α-reductase in females is responsible for lesser hair loss in them as compared to males [7]. Perturbation in aromatase level can initiate a number of diseases in both genders [4]. However, in this review some common illnesses due to hyper- and hypo-expression of aromatase has been discussed and a suite of hypotheses have been proposed. Fig. 1 illustrates the gender-specific and gender-neutral effects of the hyper and hypo level of aromatase.
Discussion The pivotal role of aromatase in health can be analyzed from a larger context. It regulates estrogen biosynthesis [105], which controls almost all aspects of a human health [106]. Hyper as well as hypo activity of aromatase is harmful for both genders. Estrogen therapy has been proven effective in birth control, Alzheimer’s, schizophrenia, osteoporosis etc. The administration of estrogen might be healing the conditions/pathologies but then it induces feminization in males [62] and cancerous proliferation in females. So, aromatse-estrogen-gender-cancer risk are tied together. Regulation of aromatase gene expression in human tissues is complex, involving alternative promoter sites that provide tissue-specific control [107]. As aromatase controls many other known and unknown metabolic pathways, inhibition of aromatase is dangerous [108]. Molecular dynamics (MD) simulations, homology modelling technique, and crystal structure determination might furnish further information on this enzyme. Another least-investigated aspect of aromatase is its role in virulence of bacterial and fungal pathogens. Synthesis of oxytetracycline, a polyketide antibiotic secreted by Streptomyces rimosus is catalyzed by the microbial bifunctional cyclase/aromatase enzyme [109]. This enzyme controls the aromatic ring formation [110]. Synthesis of anthraquinones, a type of phenolic compounds secreted by entomopathogenic bacterium Photorhabdus luminescens is also catalysed by this enzyme [111]. It suggests that pathogen aromatase enzyme might be responsible for drug degradation, and consequent drug resistance. Hence, pathogen aromatase might be developed as a potential drug target against pathogens. Also, antibiotics, the metabolic product of this dual enzyme are likely to be inducing the enhanced expression of host aromatase activity, leading to immune activation and activation.