# Coenzyme Q at the Hinge of Health and Metabolic Diseases
## 2 Biosynthesis of CoQ  
Although CoQ can be incorporated through the diet, most of the CoQ is endogenously produced inside the mitochondria of every cell and then distributed throughout the cellular membranes [15]. An overview of the CoQ biosynthesis pathway in mammals is depicted in Figure 1. The biosynthesis pathway, in which at least 13 genes are involved [16; 17; 18], is not fully understood, and most of the recent discoveries in humans comes from the study of CoQ deficiency syndrome [19]. Final reactions of CoQ biosynthesis take place inside mitochondria by a nuclear-encoded COQ proteins cluster, after the isoprenoid tail and benzoquinone head are bound, producing decaprenyl hydroxybenzoic acid (DPHB) at the matrix side of the inner mitochondrial membrane (IMM). A CoQ polyisoprenoid chain is produced through the mevalonate pathway in the endoplasmic reticulum shared with the synthesis of other lipids, such as cholesterol or dolichol, and heme A and protein prenylation [5]. It is initiated by the condensation of three acetyl-Coenzyme A (acetyl-CoA) molecules to form 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) due to acetacetyl-CoA thiolase and HMG-CoA synthase activities. Mevalonate is then produced from HMG-CoA by HMG-CoA reductase. Mevalonate is phosphorylated and decarboxylated to produce isopentenyl pyrophosphate (IPP). Farnesyl pyrophosphate synthase uses IPP to make farnesyl pyrophosphate (FPP), an intermediary product for geranyl pyrophosphate (GPP) production. The next enzyme involved in CoQ biosynthesis is transprenyl-transferase that converts FPP into polyprenyl-PP, which is considered a rate-limiting step [6]. The transport of FPP into mitochondria is not fully understood yet, but it has been proposed to occur in the ER-mitochondria contacts through the ERMES complex [17; 20; 21]. COQ1 (PDSS1 and PDSS2) would assemble the side chain producing decaprenyl-PP (DPP) in those species containing CoQ\({}_{10}\)[16; 22]. The ring precursor _para_-hydroxybenzoate (\(p\)HB) seems to be synthesized in cytosol including seven proteins, such as Hfd1p and its human homolog ALDH3A1 [23; 24]. Recently, it has been shown in yeast that the five aminotransferase, Aro8, Aro9, Bat2, Bna3, and Aat2, are required to produce the benzoquinone ring for CoQ synthesis, which would also be studied in undiagnosed CoQ deficiency syndrome [25]. Figure 1: Scheme of CoQ synthesis in mitochondria. (**A**) Synthesis of the mevalonate chain in the ER and quinone head processing from tyrosine in cytosol or mitochondrial matrix. (**B**) Assembly of benzene ring and isopenoid tail at the inner mitochondrial membrane and further modifications of the phenol head at the inner mitochondrial membrane. Members of the CoQ-synthome are indicated in each step. In some cases, the enzyme involved in some of the steps are unknown. Regulatory enzymes such as COQ8 and COQ9 are indicated at the steps in which they are actively involved. The next set of reactions occur through the interaction of \(COQ\) gene-encoded proteins that provide support for the existence of a CoQ biosynthesis complex or CoQ syntohome [17; 26]. In these reactions, a sequential series of modifications of the aromatic ring are performed. Initially, DPHB suffers from C5-hydroxylation by COQ6, resulting in decaprenyl-dihydroxybenzoate (DPDHB) formation [27]. Subsequently, DPDHB is O-methylated by COQ3 to form decaprenyl-vanillic acid (DPVA) [28; 29]. Later, a C1-hydroxylation and a C1-decarboxylation are catalyzed by unidentified proteins to form demethyl-decenylme Q (DDMQ). Afterwards, COQ5 carries a C2-methylation to form demethyl-coenzyme Q (DMQ) [30]. Thereafter, DMQ is C6-hydroxylated by COQ7 to form demethyl-coenzyme Q (DMQ) [31]. Finally, COQ3 catalyzes the final step ending in CoQ from DMQ. In recent years, other COQ proteins showing regulatory functions have been discovered. COQ8A (ADCK3) and COQ8B (ADCK4) show properties of atypical kinases that phosphorylate COQ3, COQ5, and COQ7 [32; 33; 34].