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Allantoin, a Potential Metabolite That Promotes AMPK Phosphorylation and Suppresses Cholesterol Biosynthesis Via the Mevalonate Pathway and Bloch Pathway

Yap PG, Choi SB, Liong MT

Appl Biochem Biotechnol, 2020 May;191(1):226-244.
PMID: 32125649 DOI: 10.1007/s12010-020-03265-2

This study aimed to evaluate the effect of probiotic administration on obese and ageing models. Sprague Dawley rats were subjected to high-fat diet (HFD) and injected with D-galactose to induce premature ageing. Upon 12 weeks of treatment, the faecal samples were collected and subjected to gas chromatography-mass spectrophotometry (GC-MS) analysis for metabolite detection. The sparse partial least squares discriminant analysis (sPLS-DA) showed a distinct clustering pattern of metabolite profile in the aged and obese rats administered with probiotics Lactobacillus plantarum DR7 and L. reuteri 8513d, particularly with a significantly higher concentration of allantoin. Molecular docking simulation showed that allantoin promoted the phosphorylation (activation) of adenosine monophosphate-activated kinase (AMPK) by lowering the substrate free energy of binding (FEB) and induced the formation of an additional hydrogen bond between Val184 and the substrate AMP. Allantoin also suppressed cholesterol biosynthesis by either inducing enzyme inhibition, occupying or blocking the putative binding site to result in non-spontaneous substrate binding, as in the cases of 3-hydroxy-methylglutaryl-coA reductase (HMGCR), mevalonate kinase (MVK) and lanosterol demethylase (LDM) where positive FEBs were reported. These results demonstrated the potential of allantoin to alleviate age-related hypercholesterolaemia by upregulating AMPK and downregulating cholesterol biosynthesis via the mevalonate pathway and Bloch pathway.

Matched MeSH terms: Mevalonic Acid/metabolism*
Fulltext Redirecting Metabolic Flux towards the Mevalonate Pathway for Enhanced β-Carotene Production in M. circinelloides CBS 277.49

Naz T, Nazir Y, Nosheen S, Ullah S, Halim H, Fazili ABA, et al.

Biomed Res Int, 2020;2020:8890269.
PMID: 33457420 DOI: 10.1155/2020/8890269

Carotenoids produced by microbial sources are of industrial and medicinal importance due to their antioxidant and anticancer properties. In the current study, optimization of β-carotene production in M. circinelloides strain 277.49 was achieved using response surface methodology (RSM). Cerulenin and ketoconazole were used to inhibit fatty acids and the sterol biosynthesis pathway, respectively, in order to enhance β-carotene production by diverting metabolic pool towards the mevalonate pathway. All three variables used in screening experiments were found to be significant for the production of β-carotene. The synergistic effect of the C/N ratio, cerulenin, and ketoconazole was further evaluated and optimized for superior β-carotene production using central composite design of RSM. Our results found that the synergistic combination of C/N ratios, cerulenin, and ketoconazole at different concentrations affected the β-carotene productions significantly. The optimal production medium (std. order 11) composed of C/N 25, 10 μg/mL cerulenin, and 150 mg/L ketoconazole, producing maximum β-carotene of 4.26 mg/L (0.43 mg/g) which was 157% greater in comparison to unoptimized medium (1.68 mg/L, 0.17 mg/g). So, it was concluded that metabolic flux had been successfully redirected towards the mevalonate pathway for enhanced β-carotene production in CBS 277.49.

Matched MeSH terms: Mevalonic Acid/metabolism*
Fulltext Engineering the lactococcal mevalonate pathway for increased sesquiterpene production

Song AA, Abdullah JO, Abdullah MP, Shafee N, Othman R, Noor NM, et al.

FEMS Microbiol Lett, 2014 Jun;355(2):177-84.
PMID: 24828482 DOI: 10.1111/1574-6968.12469

Isoprenoids are a large, diverse group of secondary metabolites which has recently raised a renewed research interest due to genetic engineering advances, allowing specific isoprenoids to be produced and characterized in heterologous hosts. Many researches on metabolic engineering of heterologous hosts for increased isoprenoid production are focussed on Escherichia coli and yeasts. E. coli, as most prokaryotes, use the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway for isoprenoid production. Yeasts on the other hand, use the mevalonate pathway which is commonly found in eukaryotes. However, Lactococcus lactis is an attractive alternative host for heterologous isoprenoid production. Apart from being food-grade, this Gram-positive prokaryote uses the mevalonate pathway for isoprenoid production instead of the MEP pathway. Previous studies have shown that L. lactis is able to produce sesquiterpenes through heterologous expression of plant sesquiterpene synthases. In this work, we analysed the gene expression of the lactococcal mevalonate pathway through RT-qPCR to successfully engineer L. lactis as an efficient host for isoprenoid production. We then overexpressed the mvk gene singly or co-expressed with the mvaA gene as an attempt to increase β-sesquiphellandrene production in L. lactis. It was observed that co-expression of mvk with mvaA doubled the amount of β-sesquiphellandrene produced.

Matched MeSH terms: Mevalonic Acid/metabolism*
Fulltext Overexpressing 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) in the lactococcal mevalonate pathway for heterologous plant sesquiterpene production

Song AA, Abdullah JO, Abdullah MP, Shafee N, Othman R, Tan EF, et al.

PLoS One, 2012;7(12):e52444.
PMID: 23300671 DOI: 10.1371/journal.pone.0052444

Isoprenoids are a large and diverse group of metabolites with interesting properties such as flavour, fragrance and therapeutic properties. They are produced via two pathways, the mevalonate pathway or the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway. While plants are the richest source of isoprenoids, they are not the most efficient producers. Escherichia coli and yeasts have been extensively studied as heterologous hosts for plant isoprenoids production. In the current study, we describe the usage of the food grade Lactococcus lactis as a potential heterologous host for the production of sesquiterpenes from a local herbaceous Malaysian plant, Persicaria minor (synonym Polygonum minus). A sesquiterpene synthase gene from P. minor was successfully cloned and expressed in L. lactis. The expressed protein was identified to be a β-sesquiphellandrene synthase as it was demonstrated to be functional in producing β-sesquiphellandrene at 85.4% of the total sesquiterpenes produced based on in vitro enzymatic assays. The recombinant L. lactis strain developed in this study was also capable of producing β-sesquiphellandrene in vivo without exogenous substrates supplementation. In addition, overexpression of the strain's endogenous 3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR), an established rate-limiting enzyme in the eukaryotic mevalonate pathway, increased the production level of β-sesquiphellandrene by 1.25-1.60 fold. The highest amount achieved was 33 nM at 2 h post-induction.

Matched MeSH terms: Mevalonic Acid/metabolism*
Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Hasan WNW, Chin KY, Jolly JJ, Ghafar NA, Soelaiman IN

Endocr Metab Immune Disord Drug Targets, 2018;18(5):450-457.
PMID: 29683099 DOI: 10.2174/1871530318666180423122409

BACKGROUND: Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.
OBJECTIVE: This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.
DISCUSSION: Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.
CONCLUSION: Mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

Matched MeSH terms: Mevalonic Acid/metabolism*
Fulltext Metabolic routes affecting rubber biosynthesis in Hevea brasiliensis latex

Chow KS, Mat-Isa MN, Bahari A, Ghazali AK, Alias H, Mohd-Zainuddin Z, et al.

J Exp Bot, 2012 Mar;63(5):1863-71.
PMID: 22162870 DOI: 10.1093/jxb/err363

The cytosolic mevalonate (MVA) pathway in Hevea brasiliensis latex is the conventionally accepted pathway which provides isopentenyl diphosphate (IPP) for cis-polyisoprene (rubber) biosynthesis. However, the plastidic 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway may be an alternative source of IPP since its more recent discovery in plants. Quantitative RT-PCR (qRT-PCR) expression profiles of genes from both pathways in latex showed that subcellular compartmentalization of IPP for cis-polyisoprene synthesis is related to the degree of plastidic carotenoid synthesis. From this, the occurrence of two schemes of IPP partitioning and utilization within one species is proposed whereby the supply of IPP for cis-polyisoprene from the MEP pathway is related to carotenoid production in latex. Subsequently, a set of latex unique gene transcripts was sequenced and assembled and they were then mapped to IPP-requiring pathways. Up to eight such pathways, including cis-polyisoprene biosynthesis, were identified. Our findings on pre- and post-IPP metabolic routes form an important aspect of a pathway knowledge-driven approach to enhancing cis-polyisoprene biosynthesis in transgenic rubber trees.

Matched MeSH terms: Mevalonic Acid/metabolism*