Monacolins in Red Yeast Rice Extract

1.2. Monacolins in RED YEAST RICE EXTRACT (RYR)

RED YEAST RICE EXTRACT (RYR) contains several types of secondary metabolites that have biological activity, including Monascus pigments, monacolins, gamma-aminobutyric acid, dimerumic acid, enzymes, polysaccharides, ergosterol, polyketides, unsaturated fatty acids, phytosterols, isoflavones, alkaloid, and trace elements [15,16,17]. Secondary metabolites in RED YEAST RICE EXTRACT (RYR) have been shown to have biological activities through modern pharmacological experiments. For instance, Monascus pigments (MPs) are usually used as colorants in the food and textile industries, but research has also demonstrated that they can have effects such as anti-obesity, lipid-lowering and attenuating nonalcoholic fatty liver disease in mice [18,19,20]. On the other hand, in RED YEAST RICE EXTRACT (RYR), there is a compound named citrinin that is a highly toxic, mutagenic, and carcinogenic metabolite [21]. It is worth noting that monacolin K has been researched in depth [22].

1.2.1. Physical and Chemical Properties of Monacolin K

Monacolin K is the first reported lipid-lowering component to be isolated from Monascus purpureus [23]. Monacolin K, which appears as colorless crystals, is soluble in methanol, ethanol, acetone, chloroform, and benzene but not soluble in n-hexane or petroleum ether. The boiling point is 157–159 °C and the [α]25D value is +307.6 °C (in methanol). The molecular formula is C24H36O5 (Mw 404) and the ratio of C:H:O is 71.31:8.91:19.78, obtained by elemental analysis and high-resolution mass spectroscopy. The Rf value in TLC is 0.47 in dichioromethane: acetone (4: 1, v/v). The UV spectrum (methanol) showed maxima at 229, 237, and 246 nm. The IR spectrum (KBr) showed absorption bands at 3550, 2970, 1696, and 1220 cm−1. The 13C-NMR spectrum (CD3OD) indicated the presence of two ester carbonyl carbons, four methyl carbons and methylene and methine carbons. The mass spectrum peaks (m/e) are at 404 (M+), 302 (M − 102), 284 (M − 120), and 224 (M − 180), and prominent peaks in the mass spectrum of monacolin K were observed at 198 (M − 206), 172 (M − 232), 159 (M − 245), and 157 (M − 247) [7]. There are two chemical structures in functional RED YEAST RICE EXTRACT (RYR), shown in Figure 1, the acid and lactone forms of monacolin K.

1.2.2. The Mechanism of Lipid Lowering of Monacolin K

The mechanism of lipid lowering of monacolin K is shown in Figure 2 [24]: competitively inhibiting endogenous cholesterol synthesis speed limit enzyme (3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key enzyme in cholesterol biosynthesis in animals and humans), blocking the pathways of hydroxyl valeric acid metabolic in cells, reducing cholesterol synthesis in the cell, stimulating the quantity and activity of LDL receptors on the cell membrane surface, and removing the serum cholesterol. RED YEAST RICE EXTRACT (RYR) can also inhibit the absorption of cholesterol, and the active ingredient may be sterols [24]. In the procedure, the mean serum total cholesterol (TC) and triglyceride (TG) levels decline and the low-density lipoprotein (LDL, the bad lipoprotein) level decreases significantly, but the high-density lipoprotein (HDL, the good lipoproteins) level does not change much [25]. The acid form is the efficient form because its structure is similar to that of HMG-CoA, shown in Figure 3, and can directly inhibit the synthesis of cholesterol [26]. Therefore, the lactone form needs to be hydrolyzed into an acid structure by the action of the hydroxyl esterase in the body, and then to be functionalized.

Figure2. RED YEAST RICE EXTRACT (RYR) effects on cholesterol biosynthesis
Figure 3. The HMG-CoA reductase reaction and the competitive inhibition of monacolin K acid.

1.2.3. Monacolin Analogs

In addition, there are reports showing that there are other monacolins in RED YEAST RICE EXTRACT (RYR) [27]. Evaluating the activity of newly discovered compounds in vitro, new monacolins extracted from RED YEAST RICE EXTRACT (RYR) had a similar lipid-lowering effect to monacolin K [28]. In the 1980s, Endo isolated monacolin J, L, X, M, and dihydromonacolin L from Monascus purpureus, and proved that all of them also could inhibit HMG CoA reductase and reduce the serum LDL and TC levels [29,30,31]. In 2004, Li et al. [32] identified 14 monacolin compounds such as monacolin K, J, L, M, X, and their hydroxy acid form, as well as dehydromonacolin K, dihydromonacolin L, compactin, 3α-hydroxy-3,5-dihydromonacolin L, etc. in RED YEAST RICE EXTRACT (RYR). In 2006, Dhale et al. [33] separated dihydromonacolin MV in RED YEAST RICE EXTRACT (RYR). In 2011 and 2013, Liu et al. [34,35] isolated monacophenyl, monacolin O and P from RED YEAST RICE EXTRACT (RYR). In 2012, Zhu et al. [36] extracted two new dehydromonacolins (dehydromonacolin N, J) and detected 10 other monacolins (α,β-dehydrodihydromonacolin K, L, and the ethyl ester of monacolin K, etc.) from RED YEAST RICE EXTRACT (RYR). In 2016 Zhang et al. [15] obtained new five monacolins, including monacolin R, α,β-dehydro-monacolin Q, monacolin Q, α,β-dehydro-monacolin S, and monacolin S. In 2017, Zhang et al. [37] found four new monacolins, including monacolin T, monacolin U, 6aO-methyl-4,6-dihydromonacolin L, and 6aO-ethyl-4,6-dihydromonacolin L. The chemical structures of the monacolins investigated in RED YEAST RICE EXTRACT (RYR) are shown in Table 1. What is even more remarkable is that Li et al. [38] isolated more than 80 kinds of monacolins from the RED YEAST RICE EXTRACT (RYR) product Xuezhikang and established a database of more than 720 potential monacolins, providing a potential effective method for the discovery of new analogous series, and offering a material basis for the further exploitation of RED YEAST RICE EXTRACT (RYR) products.

1.3. The Biosynthetic Pathway and Sources of Monacolin K

There are few studies about the biosynthetic pathway of monacolin K generated by Monascus purpureus, it is just speculated that this pathway may be similar to the synthetic pathway of monacolin K in Aspergillus terreus [39]. Aspergillus terreus has been frequently utilized to figure out the synthesis of monacolin K [40]. The synthetic pathway of monacolin K in Aspergillus terreus, shown in Figure 4 is as follows: (1) the lovastatin nonaketide synthase (LNKS) catalyzes the synthesis of one molecule of malonyl CoA in condensation reaction with nine molecules of acetyl CoA, generating dihydromonacolin L (a nonaketide compound) that is a main structure of monacolin K, then it formed monacolin L by oxidation, dehydration, and other steps, and finally monacolin J is generated through single oxygenase catalytic hydroxylation reaction; (2) the lovastatin diketide synthase (LDKS) catalyzes the condensation of one molecule of malonyl CoA with two molecules of acetyl CoA to form methylbutyryl CoA; (3) under the action of the transesterase, methylbutyryl CoA is linked to monacolin J with an ester ether bond to complete the synthesis of monacolin K.

Meanwhile, commercial lovastatin appeared as a lipid-lowering drug in the pharmaceutical market with the permission of the FDA in 1986. The sources of commercial lovastatin mainly contain two synthetic approaches. The first is that utilize submerged fermentation (SmF) of Monascus purpureus and Aspergillus terreus, adding carbon and nitrogen source (such as glucose, oat meal, and corn steep liquor) to medium with Monascus purpureus and Aspergillus terreus, after appropriate fermentation, then obtaining lovastatin via separation and purification; the other is chemical synthesis, replacing the decaline ring of the fungal compounds with an aromatic ring, like fluvastatin and atorovastatin [41,42]. Early studies have shown that the structure of monacolin K is chemically identical to that of commercial lovastatin [32].

In common RED YEAST RICE EXTRACT (RYR), monacolin K cannot be produced or is very tiny in a short and simple process of fermentation. Recently researchers reported that commercial lovastatin is added to common RED YEAST RICE EXTRACT (RYR) to imitate functional RED YEAST RICE EXTRACT (RYR) and therefore obtain more profits [43,44]. This phenomenon has inhibited the development of functional RED YEAST RICE EXTRACT (RYR), and more important, long-term use of lovastatin probably can cause burnout, gastrointestinal reactions, myalgia, etc. About 10–15% patients with dyslipidemia who take statins experience skeletal muscle problems [11].

Jiawen Song, Jia Luo, Zubing Ma, Qiang Sun, Chunjie Wu,* and Xiaofang Li*

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Molecules. 2019 May; 24(10): 1944.

Published online 2019 May 20. doi: 10.3390/molecules24101944

PMCID: PMC6572552;  PMID: 31137594