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Byline: J. Chang, Y. Ning, F. Xu, S. Cheng and X. Li


Terpenoids are synthesized in plants via the mevalonate (MVA) and the methylerythritol phosphate (MEP) pathways, with isopentenyl diphosphate (IPP) as the main intermediate metabolite. 3-Hydroxy-3-methylglutaryl-Coenzyme A synthase(HMGS) is the second enzyme in MVA pathway of isoprenoid biosynthesis, and catalyzes the condensation of acetyl-CoA with acetoacetyl-CoA to yield HMG-CoA.A growing body of evidence now indicates that HMGS plays significant roles in biosynthesis of terpenoids in plants. The sequences and structures of HMGS genes isolated from most plants are highly homologous. HMGS has been found to be expressed in most organs of plants, and its expression correlates strongly with accumulation of terpenoids in plants. This review focus on the research progress in the biological significance, protein structure, regulatory mechanism, gene characterization and functional analysis of HMGS in plant.

The studies on the gene family encoding HMGS has provided valuable insights into its function, phylogeny, and regulation of terpenoid content in plants.

Key words: Terpenoids; HMGS; HMG-CoA; biosynthetic pathway; expression.


Terpenoids are the most diverse class of secondary metabolites in plants (Yonekura-Sakakibara and Saito, 2009). More than 25000 types of terpenoids have been identified so far in plants. Terpenoids possess multiple ecophysiological functions, such as attracting pollinators, regulating plant growth and development, regulating heat tolerance of plants, resisting photooxidative stress, and providing direct and indirect plant defense (Tholl, 2006). In addition, terpenoids have been extensively utilized in spices, cosmetics, food, drug and pesticides as important raw materials,. Therefore, terpenoids possess great commercial value (Chadwick et al., 2013).

Terpenoids are synthesized in plants by two pathways, MVA (mevalonate) and MEP (2C-methyl-D- erythritol 4-phosphate). As shown in Fig. 1 (Rodriguez- Concepcion and Boronat, 2002), the MVA pathway exists in the cytosol, while the MEP pathway exists in plastids (Lichtenthaler et al., 1997). Acetyl-CoA serves as substrate in the MVA pathway to synthesize the critical precursor MVA, which is subsequently converted into dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). IPP and DMAPP are the synthetic precursors of secondary metabolites such as terpenoids including steroids (Buhaescu and Izzedine, 2007). Since this pathway is also related to the synthesis of substances such as cholesterol that affect human health, it has been studied for a long time (Miziorko, 2011). The MEP pathway was found in plants more than twenty years ago (Lichtenthaler, 1999). In this pathway, pyruvate and glyceraldehyde-3-phosphate serve as substrates, which are catalyzed by seven enzymes to synthesize IPP and DMAPP.

Plants produce many types of terpenoids that are all generated from the same precursors: IPP and its isomer DMAPP, which are catalyzed by their corresponding enzymes to synthesize geranyl diphosphate (GPP), farnesyl diphosphate (FPP) and geranylgeranyldiphosphate (GGPP; Tholl, 2006). The intermediates GPP, FPP and GGPP are catalyzed by the corresponding terpene synthase to produce all isoprenoid end products (Patra et al., 2013; Vranova et al., 2013). The two pathways of terpenoid synthesis in plants are not fully independent, as evidence of cross-talk between IPP in the cytosolic and plastidial pathways have been found (Hemmerlin et al., 2003; Laule et al., 2003; Dudareva et al., 2005). As the first catalyzing enzyme in the MVA pathway, HMGS plays an important role in the biosynthesis of terpenoids in plants (Rodriguez- Concepcion and Boronat, 2002).

Recently, Liao et al. (2014) summarized the past investigations on eukaryotic HMGS with particular focus on advance of plant HMGS study by researchers in China. To provide more detailed progress in plant HMGS research, this article provides a comprehensive review on research conducted to date on the biological significance, catalytic mechanism, its regulatory mechanism and cloning, and functional analysis of HMGS in plants.

Biological significance of plant HMGS in the MVA pathway: As an important condensing enzyme in the MVA pathway, HMGS can catalyze condensation of acetyl-CoA and acetoacetyl-CoA to generate HMG-CoA, which is further converted into generate MVA by HMGR. The IPP of C5 skeleton is generated by pyrophosphorylation and decarboxylation of MVA, and the common precursors are supplied for the synthesis of tepenoid compounds such as mono-, sesqui-, di- and triterpenoid (McGarvey and Croteau, 1995). Rudney and Ferguson (1959) first showed that HMGS participates in the synthesis of polyisoprene and other researchers later confirmed that HMGS is involved in the second step of the catalysis through the MVA pathway (Chun et al., 2000a, 2000b).

HMGS can be classified broadly into cytosolic and mitochondrial forms (Clinkenbeard et al., 1975a, 1975b). The mitochondrial form of HMGS is only found in mammals and responsible for the synthesis of ketone bodies (Casals et al., 1992; Thompson et al., 1997). Its product HMG-CoA is broken down into acetoacetate and 2-hydroxybutyrate by HMG-CoA lyase. As the second enzyme in the MVA pathway, the cytosolic form of HMGS can catalyze acetyl-CoAto generate HMG-CoA. In addition, MVA pathway synthesizes mevalonic acid and isoprenoids (Miziorko, 2011). Since the MVA pathway exists in nearly all eukaryotes, further research is being done on the cytosolic form of HMGS than on the mitochondrial form. The entry of acetyl-CoA into the MVA pathway is controlled by HMGS through generating HMG-CoA which is utilized by HMGR.

Structure of plant HMGS protein: The plant HMGS protein is generally composed of 460-500 amino acid residues and has a relative molecular mass of 50-60 kDa (Argout et al., 2008; Schnable et al., 2009; Schilmiller et al., 2009; Zhang et al., 2011; Kai et al., 2013). The polypeptide chain of HMGS in plants contains three domains, N-terminus, catalytic region and C-terminus. The N-terminus of HMGS in mitochondrial from contains a conservative signal peptide sequence, which mediates transport of HMGS from the cytoplasm, where it is synthesized, to the mitochondria, and shows a high degree of similarity across most plants (Hegardt, 1999). The C-terminus of HMGS contains an important catalytic cysteine residue that acts as a nuclephile in the first step of reaction: the acetylation of the enzyme by acetyl-CoA (its first substrate) to produce an acetyl-enzyme thioester, releasing the reduced coenzyme A.

The subsequent nucleophilic attack on acetoacetyl-CoA (its second substrate) leads to the formation of HMG-CoA (Theisen et al., 2004). Previous results have revealed that plant HMGS proteins are highly similar in their 3-D structures, which consist of two structural regions referred to as the upper and lower regions, similar to the HMGS from Staphylococcus aureus (Figure 2; Campobasso et al., 2004). The upper region is built around a five-layered core structure, a-AY-a-AY-a, in which each a comprises two a helices and each AY is a mixed AY-sheet. The lower region does not contain any substructure or pseudo-symmetry. However, the interface of the upper and lower regions defines the acetoacetyl-CoA-binding sites (Theisen et al., 2004).

Most HMGS proteins contain a conserved motif 'NxD/NE/VEGI/VDx(2)NACF/YxG', which is considered to be important for HMGS function (Figure 3). This motif is localized at the entrance of the active site and plays an important role in controlling the catalysis of substrates by HMGS. Mutation of this motif has been found to decrease the catalytic activity of the enzyme or to lead to formation of abnormal products. In addition, three amino acid residues, namely Cys129, His264 and Asn326, in HMGS are essential for its catalytic activity (Misra et al., 2003). The earlier report of Misra et al. (1993) showed that Cys129 participates in the formation of the intermediate compound acyl-S-enzyme as the first step of catalytic reaction of HMGS. Misra and Miziorko (1996) further showed that His264 binds directly to acetoacetyl-CoA in the second step. Based on the results of mutation analysis, Sirinupong et al. (2005) indicated that Asn326 also has an important effect on HMGS activity.

In addition, Pojer et al. (2006) determined the structure of BjHMGS1 by using protein X-ray crystallography. Cys117, His247 and Glu83 in BjHMGS1form a catalytic group common in HMGS to finish the three-stepreaction to produce HMG-CoA. These findings have deepened our understanding of the correlation between the structure and function of HMGS, which also provide important basic data for further studying the metabolic process of terpenoids.

Regulatory mechanism of HMGS in plants: HMGS participates in the synthesis of precursors of isoprenoids and provides reactive substrates for HMGR. HMGS and HMGR in plants and animals are synergistically regulated by feedback at multiple levels. For example, Schidler et al. (1985) firstly found that the specific inhibition of MVA-derived isoprenoid biosynthesis with mevinolin in radish might attributed to activity reduction of HMGS and HMGR. Subsequently, Dooley et al. (1998) demonstrated that HMGS as a key regulatory enzyme in the pathway for endogenous cholesterol synthase, was a target for negative feedback regulation by cholesterol. Moreover, Nagegowda et al. (2004) reported that Brassica juncea HMGS was inhibited by both products (HMG-CoA and CoASH) and one of the substrates (AcAc-CoA). Recently, Vranova et al. (2013) have also concluded that HMGS down-regulated at translational level possibly by MVA, which triggers a negative-feedback loop.

The results mentioned above implied that HMGS in higher plants might be is also under synergistic feedback regulation by several secondary metabolites such as isoprenoids. There are two types of feedback regulation of HMGS by metabolites (Dooley et al., 1998). The first is regulation by isoprenoids such as phytosterols on the cytosolic form of HMGS, and the second is regulation by fatty acid on the mitochondrial form of HMGS. Besides the multi-level feedback regulation by metabolites, HMGS is also under cross-regulation through other physiological pathways. For example, HMGS plays a role in the defense reaction of plants. Alex et al. (2000) reported that HMGS expression could be induced by wounding, methyl jasmonate (MJ) and salicylic acid (SA), and downregulated under abscisic acid (ABA)-induced stress and drought in B. juncea.

More recently, several groups (Zhang et al., 2011; Kai et al., 2013) also demonstrated that SA and MJ could up-regulate HMGSexpression inCamptotheca acuminate,and Salvia miltiorrhiza,respectively. In addition, the activity and expression of HMGS are also regulated by circadian rhythm. For example, Suwanmanee et al. (2004) found that the activity and mRNA expression level of HMGS in rubber latex exhibit diurnal variation, with the highest peak occurring at 02:00 AM. It is well known that blossoming of many plants and release of terpenoids by flowers follow circadian rhythm. This specific change in the release of terpenoids may be related to the time of appearance of pollinators. Therefore, we speculate that the following of circadian rhythm by HMGS expression may be related to the release of terpenoids in plants. In addition to these exogenous induction factors, HMGS expression also varies with developmental stage and differentiation.

Alex et al. (2000) studied the developmental expression pattern of HMGS in the flower, seed and seedling of B. juncea, and found that HMGS expression was the highest at early stages in these parts. In addition, HMGS expression showed correlation with rapid cell division and growth. For example, Nagegowda et al. (2005) observed that predominant localization of HMGS mRNA in the stigmas and ovules of flower buds and in the piths of seedling hypocotyls of B. juncea. The expression pattern of HMGS in plant tissues varies greatly across different plants. For example, HMGS is mainly expressed in needles, stems, hypocotyls and cotyledons, but seldom expressed in roots of C. acuminata (Kai et al., 2013) and Taxus x media (Kai et al., 2006) whereas HMGS is constitutively expressed in the leaf, stem and root of S. miltiorrhiza (Zhang et al., 2011).

Thus, the discovery of organ specificity and developmental regulation of HMGS expression provides a basis for searching the specific promoter that regulates HMGS expression and terpenoid accumulation.

Molecular cloning and functional analysis of the HMGS gene in plants: Due to its importance for terpenoid biosynthesis, HMGS is one of the most extensively studied enzymes in the MVA pathway. Since the first plant HMGS gene was cloned from Arabidopsis thaliana in 1995 (Montamat et al., 1995), scientists have cloned HMGS genes from almost 40 plants, including crops, conifers, medicinal plants, spice plants, ornamental plants and model plants (Table 1). In order to better understand the phylogenetic relationship among HMGS proteins in different plants, cluster analysis of phylogenetic tree was conducted based on the HMGS protein sequences of 29 plants. As shown in Figure 4, the HMGS sequences of phycophyta and higher plants belong to two separate branches. Chara vulgaris is a type of lower plant, and its HMGS gene is independent of other gene families.

Higher plants in the phylogenetic tree are clustered into gymnosperms and angiosperms, and angiosperms are further clustered into monocotyledons and dicotyledons. This indicates that HMGS is conserved in terms of evolutionary origin across different plants, and shows conservation of amino acid sequence and functional domain.

Montamat et al. (1995) cloned the first HMGS gene from A. thaliana, and conducted yeast complementation tests to confirm that AtHMGS has catalytic activity. Later, Wegener et al. (1997) cloned an HMGS gene induced by ozone in Pinus sylvestris, and showed that ozone might regulate isoprenoid biosynthesis by upregulating PsHMGS expression. Alex et al. (2000) cloned an HMGS gene regulated by organ development in B. juncea and induced by exogenous abiotic treatment. This indicates that HMGS may participate in the resistance of plants to environmental stresses. Results of further transgenic experiments indicated that overexpression of BjHMGS in A. thaliana not only increased sterol concentration, but also enhanced Botrytis cinerea resistance and H2O2toleranceand promoted germination in the transgenic plants (Wang et al., 2012).

Likewise, Ishiguro et al. (2010) studied the molecular mechanism of HMGS involved in development of tapetum-specific organelles and fertility of pollen grains, and found that the MVA pathway is essential for development of both tapetosomes and elaioplasts in tapetal cells and for pollen viability, at least during pollen tube elongation. Taken together, these findings indicate that HMGS plays an important role in the development and defense mechanism of plants.

The rubber secreted by Hevea brasiliensis is an important industrial material and also a type of terpenoids. Suwanmanee et al. (2002) first cloned the HMGS gene in H. brasiliensis and further research indicated that the levels of mRNA and activity of HMGS in H. brasiliensis are closely related to accumulation of rubber in the plants. Subsequently, Sirinupong et al. (2005) also isolated another HMGS gene, HMGS2, in H. brasiliensis, and the homology of nucleotide and amino acid sequences between HMGS1 and HMGS2 was found to be 92% and 94%, respectively. RT-PCR analysis showed that expression of HMGS2 in latex-producing cells and petioles were significantly higher than that in leaves, which suggests that HMGS1 and HMGS2 are two critical genes in the synthetic pathway of latex. Besides H. brasiliensis, most of the current studies on the function of HMGS in plants have focused on its effect on the metabolism of medicinal ingredients.

For instance, Zhang et al. (2011) and Kai et al. (2006, 2013) isolated the HMGS genes from three medicinal plants T. media, C. acuminata, and S. miltiorrhiza. RT-PCR analysis revealed that HMGS genes are expressed in tissue- specific manner and can be induced by exogenous factors, including SA and MJ, in these plants. However, the roles and regulatory mechanisms of HMGS genes in the biosynthesis of active constituents, including taxol, camptothecin and tanshinones, need to be further investigated in medicinal plants.

Table 1. The protein information of HMGS cloned in plants to date.

Protein name###GenBank accssion No.###Plant species###References

BjHMGS###AAF69804###Brassica juncea###Alex et al., 2000

SmHMGS###ACV65039###Salvia miltiorrhiza###Zhang et al., 2011

CaHMGS###ACD87446###Camptotheca acuminata###Kai et al., 2013

HbHMGS###AAK73854###Hevea brasiliensis###Suwanmanee et al., 2004

TmHMGS###AAT73206###TaxusA-media###Kai et al., 2006

AtHMGS###CAA58763###Arabidopsis thaliana###Montamat et al., 1995

CrHMGS###XP_006287702###Capsella rubella###Slotte et al., 2013

PsHMGS###CAA65250###Pinus sylvestris L###Wegener et al., 1997

TcHMGS###EOY24602###Theobroma cacao###Argout et al., 2008

PtHMGS###EEE79437###Populus trichocarpa###Tuskan et al., 2006

VvHMGS###CBI34763###Vitis vinifera###Jaillon et al., 2007

SgHMGS###AEM42970###Siraitia grosvenorii###Tang et al., 2011

ZmHMGS###DAA40580###Zea mays###Schnable et al., 2009

AaHMGS###ACY74339###Artemisia annua###Graham et al., 2010

CvHMGS###ABO27206###Chara vulgaris###Grauvogel and Petersen, 2007

SlHMGS###XP_004252572###Solanum lycopersicum###Schilmiller et al., 2009

RcHMGS###EEF51079###Ricinus communis

CsHMGS###AFC34137###Camellia sinensis

GmHMGS###XP_003549866###Glycine max

PpHMGS###EMJ11192###Prunus persica

PgHMGS###ADI80347###Panax ginseng

CrHMGS###AEC13715###Catharanthus roseus

FvHMGS###XP_004298742###Fragaria vesca subsp. vesca

NNHMGS###ABV02025###Nicotiana langsdorffii x

###Nicotiana sanderae

CmHMGS###XP_004511614###Cicer arietinum

MtHMGS###XP_003611167###Medicago truncatula

PkHMGS###AFP23864###Picrorhiza kurrooa

SiHMGS###XP_004957395###Setaria italica

BdHMGS###XP_003574875###Brachypodium distachyon

OsHMGS###EAZ09792###Oryza sativa Indica Group

Conclusion: Terpenoids not only play an important role in plant physiology, but also have wide applications in fields such as industry, medicine and health. Therefore, regulation of biosynthesis of terpenoids in plants is an active area of research. Significant progress has been made in our understanding of regulation and function of HMGS and its homologous genes in the past decade. However, regulation of the metabolic network involved in terpenoid metabolism in plants, especially the transcriptional regulation of enzymes (including HMGS) involved in terpenoid metabolism, requires further investigation. More specifically, the mechanism by which HMGS regulates synthesis of terpenoids at transcriptional and translational levels remains to be explored further. In addition, promoting research on the interaction network of critical proteins in the terpenoid synthetic pathway in plants is highly important.

Acknowledgments: This work was supported by the National Natural Science Foundation of China (31400603,31370680), the Natural Science Foundation of Hubei Province (2013CFA039), Key Project of Chinese Ministry of Education (212112), and International Science and Technology Cooperation Project of Hubei Province (2013BHE029 and 2013BHE039).


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Publication:Journal of Animal and Plant Sciences
Date:Oct 31, 2015

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