Phytochelatin Synthase

Abstract

Phytochelatin synthases (PC synthases) are soluble enzymes that catalyse the synthesis of heavy metal‐binding peptides termed phytochelatins (PCs) from the tripeptide glutathione (GSH) and related peptides. Though originally discovered in plants and a few fungi and characterised in terms of their role in the detoxification of nonessential heavy metal ions such as As3+, Cd2+ or Hg2+ through the heavy metal‐activated synthesis of PCs, it is now apparent that PC synthases and PC synthase (PCS)‐like enzymes, both of which deploy a Clan CA Cys protease‐type catalytic mechanism, are far more widespread and functionally versatile than was once thought. Full‐length PC synthases, consisting of a sequence‐conserved N‐terminal core catalytic domain and sequence‐variable C‐terminal domain, are found sporadically in all of the major eukaryotic taxa where they not only synthesise PCs for the detoxification of nonessential heavy metals and, as exemplified by Zn2+, the homeostasis of essential heavy metals but also participate in the cytosolic deglycination of glutathione (GS)‐conjugates and in one or more of the terminal steps underlying the innate immunity of higher plants to pathogens. Half‐length PCS‐like polypeptides, consisting of the N‐terminal catalytic domain but lacking the C‐terminal domain, are found in some bacteria, and in the one example characterised in detail catalyse a reaction strongly biased in favour of the deglycination of GSH over the synthesis of PCs. The full extent and mechanistic basis of the roles played by PC synthases as multitasking enzymes remain to be determined, but what is apparent is that the combined protease and peptide polymerase activities of the eukaryotic enzymes versus the limited protease activities of their bacterial counterparts confer a metabolic versatility on the former that the latter lack.

Key Concepts

  • Eukaryotic PC synthases catalyse the heavy metal‐activated posttranslational synthesis of short‐chain thiol‐rich γEC polymers, phytochelatins (PCs) with the general structure (γEC)nX, typically (γEC)nG, from glutathione (GSH; γECG) or related γEC‐containing peptides. PCs bind heavy metal ions with high affinity to contribute to the detoxification of nonessential heavy metals such as As3+, Cd2+ or Hg2+ and the homeostasis of essential heavy metals such as Zn2+.
  • The PC synthetic reaction catalysed by eukaryotic PC synthases is a γEC dipeptidyl transferase reaction consisting of two main phases: the initial cleavage (deglycination) of GSH or related γEC‐containing peptides to yield γEC followed by transfer of the γEC unit to the N‐terminus of another GSH molecule or a preexistent PC.
  • Eukaryotic PC synthases are dimeric proteins made up of two identical 50–55 kDa subunits, each of which consists of a sequence‐conserved 220–240 amino acid residue N‐terminal domain and a sequence‐variable 200–270 amino acid residue C‐terminal domain. The N‐terminal domain, alone, is sufficient for heavy metal‐activated PC synthesis, but the exact role played by the C‐terminal domain, other than in influencing the specificity and extent of catalytic activation by heavy metals in vitro and processes related to the innate immunity of plants to microbial pathogens, is unknown.
  • Steady‐state PC synthesis by eukaryotic PC synthases is by a ping‐pong (substituted enzyme) mechanism. In the first phase of the reaction, a γEC‐enzyme covalent intermediate is formed when the first substrate, the γEC donor (e.g. GSH), undergoes cleavage (deglycination) with the release of free Gly. In the second phase of the reaction, the γEC unit on the enzyme is transferred to the second substrate, the acceptor (e.g. bis(glutathionato)cadmium, CdGS2), concomitant with the formation of a γ‐peptide bond between the γEC unit and the N‐terminal Glu residue of GSH. Activation of core catalysis is contingent on the provision of a substrate pair in which the thiol groups of at least one of the two substrates are blocked through the formation of a metal thiolate or S‐alkylation. Although GSH and its corresponding heavy metal thiolates (e.g. Cd.GS2) are the usual substrates for this reaction, S‐alkyl GSH derivatives can substitute for both substrates.
  • Members of the PC synthase family are not only found in representatives of all of the major eukaryotic taxa but also sporadically as PC synthase (PCS)‐like polypeptides in bacteria. Unlike all known eukaryotic PC synthases, which are full‐length molecules consisting of both the N‐terminal core catalytic and C‐terminal domains, their bacteria PCS‐like homologs are half‐molecules lacking the C‐terminal domain.
  • As exemplified by the PCS‐like polypeptide from the cyanobacterium Nostoc sp. PCC 7120 (NsPCS), the enzymes from bacteria, unlike their equivalents from eukaryotes, catalyse only the first phase of the PC synthetic reaction, the deglycination of GSH to yield γEC.
  • The N‐terminal domains of eukaryotic PC synthases and the PCS‐like polypeptides of bacteria deploy a catalytic mechanism similar to that of the Clan CA Cys proteases papain, staphopain and cruzain. All of these enzymes possess a Cys‐His‐Asp/Asn catalytic triad, the Cys residue of which through cooperative interactions with the His and Asp/Asn residues undergoes acylation to generate an enzyme thioester.
  • The essential difference between catalysis by Clan CA Cys proteases, NsPCS and eukaryotic PC synthases is the identity of the second substrate. Clan CA Cys proteases and NsPCS catalyse α‐peptide hydrolysis by nucleophilic attack on the enzyme thioester intermediate by water, so precluding downstream γ‐peptide bond formation, whereas eukaryotic PC synthases are capable of catalysing nucleophilic attack on the thioester enzyme intermediate by a second thiol derivative concomitant with condensation of the γEC unit from the first substrate with the second substrate through the formation of a γ‐peptide bond.
  • Eukaryotic PC synthases are not only responsible for the synthesis of PCs for the detoxification of nonessential and homeostasis of essential heavy metals but are also involved in the cytosolic processing of glutathione S‐conjugates generated through the action of glutathione S‐transferases (GSTs). This they do through deployment of the first of the two phases of the PC synthetic reaction – deglycination of the GS substituent of the conjugate. The full significance of this capability is unknown, but its potential is considerable in that the GST‐mediated synthesis of GS‐conjugates is a critical preparatory step for the metabolism and/or detoxification of a broad range of endogenous secondary metabolites and xenobiotics.
  • PC synthases are implicated in the innate immune response of higher plants to microbial pathogens. The steps in innate immunity in which the enzyme participates, for instance the processing of antimicrobial compounds, appear to map to the C‐terminal domain of the plant enzyme.

Keywords: phytochelatin (PC) synthase; phytochelatins (PCs); phytochelatin synthase (PCS)‐like polypeptides; catalytic mechanism; cysteine protease; Cys‐His‐Asp catalytic triad; heavy metal detoxification; zinc homeostasis; glutathione (GS)‐conjugate catabolism; plant innate immunity

Figure 1. Phytochelatin structure and synthesis. (a) General structure of a phytochelatin (PC). The example shown is PC2, which contains two γEC repeats. Most PCs are derived from glutathione (γECG), have the general structure γ(EC)nG and usually contain 2–5 but sometimes as many as 15 γEC repeats. (b) Overall PC synthetic reaction catalysed by PC synthase. The usual PC synthetic reaction is a heavy metal‐, for instance Cd2+‐, activated dipeptidyl transfer reaction in which a γEC unit is transferred from one GSH donor molecule to another to yield PC2 or to a preexistent PC (the acceptor; PC2 in this example) to yield a PC extended by one γEC unit (PC3 in this example) concomitant with the release of a Gly residue from the donor. Unlike translationally synthesised peptides, the N‐termini of PCs have a free α‐carboxyl as well as a free α‐amino group, and the peptide bonds connecting the γEC units are γ‐ rather than α‐peptide bonds. Reproduced by permission of Sara Jarret, CMI.
Figure 2. Comparison of PC synthase polypeptides and their derivatives. The examples shown are the full‐length eukaryotic PC synthases from Arabidopsis (AtPCS1), S. pombe (SpPCS) and C. elegans (CePCS1), the bacterial half‐length PCS‐like polypeptide from Nostoc sp. PCC 7120 (NsPCS), two C‐terminally truncated derivatives from V8 protease‐digested native AtPCS1 (PCS1_Nt1 and PCS1_Nt2) and a C‐terminally truncated version of AtPCS1 containing only the first 221 N‐terminal residues (AtPCS1_221tr). The approximate positions of all of the Cys residues are indicated by white bars and of the conserved His and Asp residues in the N‐terminal domain by blue and red bars, respectively. AtPCS1 residues Cys56, His162 and Asp180 are the catalytic triad residues that are conserved in all known PC synthases and align with the catalytic triad residues of Clan CA Cys proteases. Sequence‐conserved N‐terminal domains are shown in dark grey; sequence‐variable C‐terminal domains are shown in light grey. Numbers on the right denoted the total number of residues in each polypeptide. Reproduced by permission of Sara Jarret, CMI.
Figure 3. Comparison of Clan CA Cys proteases, eukaryotic PC synthases and the bacterial PCS‐like polypeptide NsPCS. (a) Alignment of Clan CA proteases of known structure (papain, PDB code 1PE6; cruzain, PDB code 1AIM; staphopain, PDB code 1CV8) with AtPCS1, CePCS1, SpPCS and NsPCS (alias Alr0975, PDB code 2BTW) within the vicinity of the active site residues shown in panel c. (b) Crystal structure of γEC‐thioester of NsPCS (Vivares et al., ). One of the two monomers is shown as a ribbon structure; the other is shown as the solvent‐accessible structure. Red and grey patches in the solvent‐accessible structure denote residues that are identical and similar, respectively, between NsPCS and its eukaryotic homologs; yellow patches denote residues that are unique to NsPCS. The positions of the γEC groups of the enzyme Cys70‐thioester intermediate, one on each subunit, are delimited by blue circles. (c) Active site residues of NsPCS (structures and text in green), papain (structures and text in grey) and AtPCS1 (text in red) inferred from the crystal structures of NsPCS and papain and from site‐directed mutagenesis of AtPCS1. Reproduced by permission of Sara Jarret, CMI.
Figure 4. Schematic representation of tentative catalytic mechanism of PC synthase‐catalysed PC synthesis as exemplified by AtPCS1. Initial nucleophilic attack of the peptide bond that is to be cleaved in GSH (or a preexistent PC; the γEC donor) in the first phase of the reaction is by Cys56 to yield acyl‐AtPCS1, a γEC‐Cys56 thioester, concomitant with the release of free Gly from the C‐terminus of the donor (1). As explained in the text, the unusual reactivity of this particular Cys residue is attributable to its immediate adjacency to His162 and Asp180, the other two members of the catalytic triad within the active site of the enzyme. In the second phase of the reaction, the enzyme‐associated γEC group undergoes nucleophilic attack by the N‐terminal amino group of another GSH (or another PC) molecule (the γEC acceptor) (2) to yield PC2 (or a PCn molecule further extended by another γEC unit) through the formation of a new peptide concomitant with cleavage of the γEC‐Cys56 thioester bond (3). When the PC2 (or PCn+1) product dissociates from the active site to be replaced by a new γEC donor, the catalytic cycle is completed (4). In the first phase of the reaction, the proton released from the Cys56‐SH group (–SH → –S + H+) is transferred to His162 and then to the N‐terminal amino group of Gly; in the second phase of the reaction, the proton regained by the Cys56‐SH group is derived from the N‐terminal amino group of the second substrate (–S–γEC + –NHH+– → –SH + γEC–NH–). ∼∼, γ‐peptide bond. Reproduced by permission of Sara Jarret, CMI.
Figure 5. GS‐conjugate catabolism in plants. Electrophilic compounds (R), as exemplified by the herbicide safener fenclorim (a), are conjugated with GSH (γECG) by glutathione S‐transferases (GSTs) to yield GS‐conjugates that undergo degradation by alternate pathways (b). In animals, the degradation of GS‐conjugates is mediated by the sequential action of a γ‐glutamyl transpeptidase (GGT) and a membrane‐bound carboxypeptidase (Cys‐Gly dipeptidase; CGD) to yield Cys‐conjugates. In plants, however, there appear to be two routes (b). In one, the GS‐conjugates undergo transport into the vacuole where a γ‐glutamyl transpeptidase, GGT4, catalyses their degradation to Cys‐Gly‐conjugates which then undergo conversion to Cys‐derivatives, presumably through the action of vacuolar carboxypeptidases (VCP). In the other, GS‐conjugates appear to undergo deglycination in the cytosol by PC synthase to yield γEC‐conjugates which then undergo conversion to Cys‐conjugates through the action of a vacuolar γ‐glutamyl transpeptidase (GGT4). Reproduced by permission of Sara Jarret, CMI.
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Further Reading

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Rea, Philip A(May 2020) Phytochelatin Synthase. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028220]