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• W2008554986 abstract "Phosphatidyl-myo-inositol mannosides (PIMs) are unique glycolipids found in abundant quantities in the inner and outer membranes of the cell envelope of all Mycobacterium species. They are based on a phosphatidyl-myo-inositol lipid anchor carrying one to six mannose residues and up to four acyl chains. PIMs are considered not only essential structural components of the cell envelope but also the structural basis of the lipoglycans (lipomannan and lipoarabinomannan), all important molecules implicated in host-pathogen interactions in the course of tuberculosis and leprosy. Although the chemical structure of PIMs is now well established, knowledge of the enzymes and sequential events leading to their biosynthesis and regulation is still incomplete. Recent advances in the identification of key proteins involved in PIM biogenesis and the determination of the three-dimensional structures of the essential phosphatidyl-myo-inositol mannosyltransferase PimA and the lipoprotein LpqW have led to important insights into the molecular basis of this pathway. Phosphatidyl-myo-inositol mannosides (PIMs) are unique glycolipids found in abundant quantities in the inner and outer membranes of the cell envelope of all Mycobacterium species. They are based on a phosphatidyl-myo-inositol lipid anchor carrying one to six mannose residues and up to four acyl chains. PIMs are considered not only essential structural components of the cell envelope but also the structural basis of the lipoglycans (lipomannan and lipoarabinomannan), all important molecules implicated in host-pathogen interactions in the course of tuberculosis and leprosy. Although the chemical structure of PIMs is now well established, knowledge of the enzymes and sequential events leading to their biosynthesis and regulation is still incomplete. Recent advances in the identification of key proteins involved in PIM biogenesis and the determination of the three-dimensional structures of the essential phosphatidyl-myo-inositol mannosyltransferase PimA and the lipoprotein LpqW have led to important insights into the molecular basis of this pathway. Introductionmyo-Inositol, as a phospholipid constituent, was first reported in mycobacteria by R. J. Anderson in 1930 (1Anderson R.J. J. Am. Chem. Soc. 1930; 52: 1607-1608Crossref Scopus (8) Google Scholar). Subsequently, the presence of phosphatidyl-myo-inositol (PI) 3The abbreviations used are: PIphosphatidyl-myo-inositolPIM1PI monomannosidePIM2PI dimannosidePIM3PI trimannosidePIM4PI tetramannosidePIM5PI pentamannosidePIM6PI hexamannosideLMlipomannanLAMlipoarabinomannanBCGbacillus Calmette-Guérinα-ManTα-mannosyltransferaseGTglycosyltransferase. dimannosides (PIM2) and PI pentamannosides (PIM5) was recognized in Mycobacterium tuberculosis (2Ballou C.E. Vilkas E. Lederer E. J. Biol. Chem. 1963; 238: 69-76Abstract Full Text PDF PubMed Google Scholar, 3Lee Y.C. Ballou C.E. J. Biol. Chem. 1964; 239: 1316-1327Abstract Full Text PDF PubMed Google Scholar). Over the past 40 years, the structure of the complete family of PI mannosides (PIM1–PIM6) in various Mycobacterium spp. and related Actinomycetes has been defined, first as deacylated glycerophosphoryl-myo-inositol mannosides and later as the fully acylated native molecules (4Brennan P.J. Ratledge C. Wilkinson S.G. Microbial Lipids. Academic Press Ltd., London1988: 203-298Google Scholar).PIMs and metabolically related lipoglycans comprising lipomannan (LM) and lipoarabinomannan (LAM) are noncovalently anchored through their PI moiety to the inner and outer membranes of the cell envelope (5Ortalo-Magné A. Lemassu A. Lanéelle M.A. Bardou F. Silve G. Gounon P. Marchal G. Daffé M. J. Bacteriol. 1996; 178: 456-461Crossref PubMed Scopus (205) Google Scholar, 6Pitarque S. Larrouy-Maumus G. Payré B. Jackson M. Puzo G. Nigou J. Tuberculosis. 2008; 88: 560-565Crossref PubMed Scopus (76) Google Scholar) and play various essential although poorly defined roles in mycobacterial physiology. They are also thought to be important virulence factors during the infection cycle of M. tuberculosis. Aided by the availability of a growing number of genome sequences from lipoglycan-producing Actinomycetes, developments in the genetic manipulation of these organisms, and advances in our understanding of the molecular processes underlying sugar transfer in Corynebacterianeae, considerable progress was made over the last 10 years in identifying the enzymes associated with the biogenesis of PIM, LM, and LAM (for recent review, see Refs. 7Berg S. Kaur D. Jackson M. Brennan P.J. Glycobiology. 2007; 17 (Review): 35-56RCrossref PubMed Scopus (167) Google Scholar and 8Kaur D. Guerin M.E. Skovierová H. Brennan P.J. Jackson M. Adv. Appl. Microbiol. 2009; 69: 23-78Crossref PubMed Scopus (172) Google Scholar). The precise chemical definition of these molecules from various Actinomycetes combined with comparative analyses of their interactions with the host immune system also has shed light on their structure-function relationships (9Gilleron M. Jackson M. Nigou J. Puzo G. Daffé M. Reyrat J.M. The Mycobacterial Cell Envelope. American Society for Microbiology, Washington, D.C2008: 75-105Google Scholar).In this minireview, we present some key enzymatic, structural, and topological aspects of the biogenesis of PIMs, a pathway that may represent a paradigm for that of other mycobacterial complex (glyco)lipids. The elucidation of this pathway has helped in our understanding of the pathogenesis of tuberculosis and revealed new opportunities for drug discovery.Chemical Structure of PIMs: An OverviewThe PIM family of glycolipids comprises PI mono-, di-, tri-, tetra-, penta-, and hexamannosides with different degrees of acylation. PIM2 and PIM6 are the two most abundant classes found in Mycobacterium bovis bacillus Calmette-Guérin (BCG), M. tuberculosis H37Rv, and Mycobacterium smegmatis 607 (10Gilleron M. Quesniaux V.F. Puzo G. J. Biol. Chem. 2003; 278: 29880-29889Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). The presence of myo-inositol and mannose as sugar constituents of phospholipids from M. tuberculosis was first reported by Anderson in the 1930s (1Anderson R.J. J. Am. Chem. Soc. 1930; 52: 1607-1608Crossref Scopus (8) Google Scholar, 11Anderson R.J. Renfrew A.G. J. Am. Chem. Soc. 1930; 52: 1252-1254Crossref Scopus (3) Google Scholar, 12Anderson R.J. Roberts G. J. Am. Chem. Soc. 1930; 52: 5023-5029Crossref Scopus (5) Google Scholar, 13Anderson R.J. Prog. Chem. Org. Nat. Prod. 1939; 3: 145-202Google Scholar). Using similar approaches 25 years later, Lee and Ballou arrived at a complete structure of PIM2 from M. tuberculosis and Mycobacterium phlei and provided evidence of the existence of mono-, tri-, tetra-, and pentamannoside variants (2Ballou C.E. Vilkas E. Lederer E. J. Biol. Chem. 1963; 238: 69-76Abstract Full Text PDF PubMed Google Scholar, 3Lee Y.C. Ballou C.E. J. Biol. Chem. 1964; 239: 1316-1327Abstract Full Text PDF PubMed Google Scholar, 14Lee Y.C. Ballou C.E. Biochemistry. 1965; 4: 1395-1404Crossref PubMed Scopus (84) Google Scholar, 15Hill D.L. Ballou C.E. J. Biol. Chem. 1966; 241: 895-902Abstract Full Text PDF PubMed Google Scholar). A reanalysis of PIMs from M. smegmatis in their deacylated form later revealed a structure based on that previously defined by Ballou et al. but containing six Manp residues (PIM6) (16Chatterjee D. Hunter S.W. McNeil M. Brennan P.J. J. Biol. Chem. 1992; 267: 6228-6233Abstract Full Text PDF PubMed Google Scholar). The complete chemical structures of the acylated native forms of PIM2 and PIM6 were later reinvestigated in M. bovis BCG and unequivocally established (Fig. 1A) (10Gilleron M. Quesniaux V.F. Puzo G. J. Biol. Chem. 2003; 278: 29880-29889Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 17Gilleron M. Ronet C. Mempel M. Monsarrat B. Gachelin G. Puzo G. J. Biol. Chem. 2001; 276: 34896-34904Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). PIM2 is composed of two Manp residues attached to positions 2 and 6 of the myo-inositol ring of PI. PIM6 is composed of a pentamannosyl group, t-α-Manp(1→2)-α-Manp(1→2)-α-Manp(1→6)-α-Manp(1→6)-α-Manp(1→, attached to position 6 of the myo-inositol ring, in addition to the Manp residue present at position 2 (Fig. 1A). Brennan and Ballou (18Brennan P. Ballou C.E. J. Biol. Chem. 1967; 242: 3046-3056Abstract Full Text PDF PubMed Google Scholar) initially found that PIM2 occurs in multiple acylated forms, where two fatty acids are attached to the glycerol moiety, and two additional fatty acids may esterify available hydroxyls on the Manp residue and/or the myo-inositol ring (Fig. 1A). The tri- and tetraacylated forms of PIM2 and PIM6 (Ac1PIM2/Ac2PIM2 and Ac1PIM6/Ac2PIM6) are the most abundant. Ac1PIM2 and Ac1PIM6 from M. bovis BCG show major acyl forms containing two palmitic acid residues (C16) and one tuberculostearic acid residue (10-methyloctadecanoate, C19), where one fatty acyl chain is linked to the Manp residue attached to position 2 of myo-inositol, and two fatty acyl chains are located on the glycerol moiety. The tetraacylated forms, Ac2PIM2 and Ac2PIM6, are present predominantly as two populations bearing either three C16/one C19 or two C16/two C19 (10Gilleron M. Quesniaux V.F. Puzo G. J. Biol. Chem. 2003; 278: 29880-29889Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 17Gilleron M. Ronet C. Mempel M. Monsarrat B. Gachelin G. Puzo G. J. Biol. Chem. 2001; 276: 34896-34904Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar). Mass spectrometry analyses have led to the conclusion that the glycerol moiety is preferentially acylated with C16/C19. Other acylation positions are C3 of the myo-inositol unit and C6 of Manp linked to C2 of myo-inositol.Suggestive of a metabolic relationship, the reducing end of LM and LAM shares structural similarities with PIMs in that the myo-inositol residues of the PI of PIMs, LM, and LAM are mannosylated at positions 2 and 6, and similar fatty acyl chains esterify the glycerol moiety, Manp linked to C2 of myo-inositol, and the myo-inositol ring (16Chatterjee D. Hunter S.W. McNeil M. Brennan P.J. J. Biol. Chem. 1992; 267: 6228-6233Abstract Full Text PDF PubMed Google Scholar, 19Hunter S.W. Brennan P.J. J. Biol. Chem. 1990; 265: 9272-9279Abstract Full Text PDF PubMed Google Scholar, 20Khoo K.H. Dell A. Morris H.R. Brennan P.J. Chatterjee D. Glycobiology. 1995; 5: 117-127Crossref PubMed Scopus (116) Google Scholar, 21Nigou J. Gilleron M. Cahuzac B. Bounéry J.D. Herold M. Thurnher M. Puzo G. J. Biol. Chem. 1997; 272: 23094-23103Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar).PIM2 BiosynthesisAc1PIM2 and Ac2PIM2 are considered both metabolic end products and intermediates in the biosynthesis of Ac1PIM6/Ac2PIM6, LM, and LAM. According to the currently accepted model, PIM synthesis is initiated by the transfer of two Manp residues and one fatty acyl chain onto PI on the cytosolic face of the plasma membrane. The first step consists of the transfer of a Manp residue from GDP-Manp to position 2 of the myo-inositol ring of PI to form PI monomannoside (PIM1) (Fig. 1, A and B) (15Hill D.L. Ballou C.E. J. Biol. Chem. 1966; 241: 895-902Abstract Full Text PDF PubMed Google Scholar). On the basis of genetic, enzymatic, and structural evidence, we identified PimA from M. smegmatis (orthologous to Rv2610c of M. tuberculosis H37Rv) as the α-mannosyltransferase (α-ManT) responsible for this catalytic step and found this enzyme to be essential for the growth of M. smegmatis mc2155 and M. tuberculosis (22Korduláková J. Gilleron M. Mikusova K. Puzo G. Brennan P.J. Gicquel B. Jackson M. J. Biol. Chem. 2002; 277: 31335-31344Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 23Guerin M.E. Kaur D. Somashekar B.S. Gibbs S. Gest P. Chatterjee D. Brennan P.J. Jackson M. J. Biol. Chem. 2009; 284: 25687-25696Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). 4N. Barilone, G. Stadthagen, and M. Jackson, unpublished data. The second step involves the action of the α-ManT PimB′ (Rv2188c), also an essential enzyme of M. smegmatis, which transfers a Manp residue from GDP-Manp to position 6 of the myo-inositol ring of PIM1 (23Guerin M.E. Kaur D. Somashekar B.S. Gibbs S. Gest P. Chatterjee D. Brennan P.J. Jackson M. J. Biol. Chem. 2009; 284: 25687-25696Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 24Lea-Smith D.J. Martin K.L. Pyke J.S. Tull D. McConville M.J. Coppel R.L. Crellin P.K. J. Biol. Chem. 2008; 283: 6773-6782Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). The essential character of both PimA and PimB′ validates these enzymes as therapeutic targets worthy of further development.Both PIM1 and PIM2 can be acylated with palmitate at position 6 of the Manp residue transferred by PimA by the acyltransferase Rv2611c to form Ac1PIM1 and Ac1PIM2, respectively. The disruption of Rv2611c abolishes the growth of M. tuberculosis and severely alters that of M. smegmatis particularly at low NaCl concentrations and when detergent (Tween 80) is present in the culture medium (25Korduláková J. Gilleron M. Puzo G. Brennan P.J. Gicquel B. Mikusová K. Jackson M. J. Biol. Chem. 2003; 278: 36285-36295Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar).4 Based on cell-free assays, two models were originally proposed for the biosynthesis of Ac1PIM2 in mycobacteria. In the first model, PI is mannosylated to form PIM1. PIM1 is then further mannosylated to form PIM2, which is acylated to form Ac1PIM2. In the second model, PIM1 is first acylated to Ac1PIM1 and then mannosylated to Ac1PIM2. Recent cell-free assays using pure enzymes alone or in combination with M. smegmatis membrane extracts indicated that although both pathways might co-exist in mycobacteria, the sequence of events PI → PIM1 → PIM2 → Ac1PIM2 is favored (23Guerin M.E. Kaur D. Somashekar B.S. Gibbs S. Gest P. Chatterjee D. Brennan P.J. Jackson M. J. Biol. Chem. 2009; 284: 25687-25696Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). The acyltransferase responsible for the transfer of a fourth acyl group to position 3 of the myo-inositol ring has not yet been identified.A major advance in our understanding of the molecular basis of the biosynthesis of the PIM2 family was provided by the structural characterization of PimA from M. smegmatis mc2155 (26Guerin M.E. Kordulakova J. Schaeffer F. Svetlikova Z. Buschiazzo A. Giganti D. Gicquel B. Mikusova K. Jackson M. Alzari P.M. J. Biol. Chem. 2007; 282: 20705-20714Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). PimA is not only a key player in the biosynthetic pathway of PIM but also a paradigm of a large family of peripheral membrane-associated glycosyltransferases (GTs), the molecular mechanisms of substrate/membrane recognition and catalysis of which are poorly understood. The PimA enzyme, which belongs to the ubiquitous GT4 family of retaining GTs (CAZy (Carbohydrate-Active enZYmes) Database), displays the typical GT-B fold of GTs (Fig. 2A) (26Guerin M.E. Kordulakova J. Schaeffer F. Svetlikova Z. Buschiazzo A. Giganti D. Gicquel B. Mikusova K. Jackson M. Alzari P.M. J. Biol. Chem. 2007; 282: 20705-20714Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 27Lairson L.L. Henrissat B. Davies G.J. Withers S.G. Annu. Rev. Biochem. 2008; 77: 521-555Crossref PubMed Scopus (1276) Google Scholar). The crystal structure of a PimA·GDP-Manp complex revealed that the enzyme adopts a “closed” conformation in the presence of GDP-Manp, with the GDP moiety of the sugar donor substrate making binding interactions predominantly with the C-terminal domain of the protein (Fig. 2B). The three-dimensional structure also provided clear insights into the architecture of the lipid acceptor-binding site. Docking calculations and site-directed mutagenesis validated the position of the polar head of the lipid acceptor, myo-inositol phosphate, in a well defined pocket with its O2 atom favorably positioned to receive the Manp residue from GDP-Manp (Fig. 2B) (28Guerin M.E. Schaeffer F. Chaffotte A. Gest P. Giganti D. Korduláková J. van der Woerd M. Jackson M. Alzari P.M. J. Biol. Chem. 2009; 284: 21613-21625Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar).FIGURE 2Structural basis of PimA and LpqW. A, overall structure of PimA. The enzyme (42.3 kDa; shown in A and B in its closed conformation) displays the typical GT-B fold of GTs, consisting of two Rossmann fold domains with a deep fissure at the interface that includes the catalytic center. Met1–Gly169 and Trp349–Ser373 form the N-terminal domain of the protein (in yellow), whereas the C-terminal domain consists of Val170–Asp348 (in orange). The core of each domain is composed of seven parallel β-strands alternating with seven connecting α-helices. Two regions of the structure have poor or no electron density, indicating conformational flexibility. The conserved connecting loop β3–α2 (residues 59–70) within the N-terminal domain and the C-terminal extension of the protein (residues 374–386) that is missing in other mycobacterial PimA homologs is shown as dashed lines. B, model of action for PimA. See text for details. The secondary structure of a selected region of PimA (in a different orientation than in A) including the GDP-Manp (GDM)- and myo-inositol phosphate (IP)-binding sites and the amphipathic α2 helix involved in membrane association is shown. Membrane attachment is mediated by an interfacial binding surface on the N-terminal domain of the protein, which likely includes a cluster of basic residues and the adjacent exposed loop β3–α2. Protein-membrane interactions stimulate catalysis by facilitating substrate diffusion from the lipid bilayer to the catalytic site and/or by inducing allosteric changes in the protein. C, overall structure and proposed mode of action for LpqW. LpqW is predicted to be a monomeric membrane-associated lipoprotein composed of 600 amino acids (62.9 kDa). The crystal structure revealed that the protein is organized in two lobes. Three structural domains (I, II, and III) can be identified, with domains I (magenta) and II (orange) representing the “lower” lobe (lobe 1) and domain III (yellow) representing the “upper” lobe (lobe 2). Although the structure of LpqW was determined in the non-liganded state, the major periplasmic component of PIM4 (t-α-Manp(1→6)-α-Manp(1→6)) was accommodated by using in silico docking. It is proposed that LpqW functions at the divergence point of the polar PIM and LM/LAM biosynthetic pathways to control the relative abundance of these species in the mycobacterial cell envelope.View Large Image Figure ViewerDownload Hi-res image Download (PPT)More recently, experimental evidence based on structural, calorimetric, mutagenesis, and enzyme activity studies indicated that PimA undergoes significant conformational changes upon substrate binding that seem to be important for catalysis. Specifically, the binding of the donor substrate, GDP-Manp, triggered an important interdomain rearrangement from an “open” to a closed state that stabilized the enzyme and considerably enhanced its affinity for the acceptor substrate, PI. The interaction of PimA with the β-phosphate of GDP-Manp was essential for this conformational change to occur. The open-to-closed motion brings together critical residues from the N- and C-terminal domains, allowing the formation of a functionally competent active site. In contrast, the binding of PI to the enzyme had the opposite effect, inducing the formation of a more relaxed complex with PimA. It could be speculated that PI binding allows the initiation of the enzymatic reaction and induces the “opening” of the protein, allowing the product to be released. Interestingly, GDP-Manp stabilized and PI destabilized PimA by a similar enthalpic amount, suggesting that they form or disrupt an equivalent number of interactions within PimA complexes. Altogether, our experimental data support a model wherein flexibility and conformational transitions confer upon PimA the adaptability to the donor and acceptor substrates required for catalysis (28Guerin M.E. Schaeffer F. Chaffotte A. Gest P. Giganti D. Korduláková J. van der Woerd M. Jackson M. Alzari P.M. J. Biol. Chem. 2009; 284: 21613-21625Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). In this regard, PimA thus seems to follow an ordered mechanism similar that reported for other GT-B enzymes (29Chen L. Men H. Ha S. Ye X.Y. Brunner L. Hu Y. Walker S. Biochemistry. 2002; 41: 6824-6833Crossref PubMed Scopus (71) Google Scholar, 30Varki A. Cummings R. Esko J. Freeze H. Stanley P. Bertozzi C.R. Hart G. Etzler M.E. Essentials of Glycobiology. 2nd Ed. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY2009Google Scholar).Another key aspect of the mode of action of PimA is its interaction with membranes. To perform their biochemical functions, membrane-associated GTs interact with membranes by two different mechanisms. Whereas integral membrane GTs are permanently attached through transmembrane regions (e.g. hydrophobic α-helices) (31Morita Y.S. Sena C.B. Waller R.F. Kurokawa K. Sernee M.F. Nakatani F. Haites R.E. Billman-Jacobe H. McConville M.J. Maeda Y. Kinoshita T. J. Biol. Chem. 2006; 281: 25143-25155Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar), peripheral membrane-associated GTs temporarily bind membranes by (i) a stretch of hydrophobic residues exposed to bulk solvent, (ii) electropositive surface patches that interact with acidic phospholipids (e.g. amphipathic α-helices), and/or (iii) protein-protein interactions (32Lind J. Rämö T. Klement M.L. Bárány-Wallje E. Epand R.M. Epand R.F. Mäler L. Wieslander A. Biochemistry. 2007; 46: 5664-5677Crossref PubMed Scopus (38) Google Scholar, 33Wang X. Weldeghiorghis T. Zhang G. Imperiali B. Prestegard J.H. Structure. 2008; 16: 965-975Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 34Seelig J. Biochim. Biophys. Acta. 2004; 1666: 40-50Crossref PubMed Scopus (268) Google Scholar, 35Wieprecht T. Apostolov O. Beyermann M. Seelig J. Biochemistry. 2000; 39: 191-201Google Scholar). A close interaction of the α-ManTs PimA and PimB′ with membranes is likely to be a strict requirement for PI/PIM modification. Consistent with this hypothesis, the membrane association of PimA via electrostatic interactions is suggested by the presence of an amphipathic α-helix and surface-exposed hydrophobic residues in the N-terminal domain of the protein (Fig. 2B). Despite the fact that sugar transfer is catalyzed between the mannosyl group of the GDP-Manp donor and the myo-inositol ring of PI, the enzyme displayed an absolute requirement for both fatty acid chains of the acceptor substrate in order for the transfer reaction to take place. Most importantly, although PimA was able to bind monodisperse PI, its transferase activity was stimulated by high concentrations of non-substrate anionic surfactants, indicating that the reaction requires a lipid-water interface (26Guerin M.E. Kordulakova J. Schaeffer F. Svetlikova Z. Buschiazzo A. Giganti D. Gicquel B. Mikusova K. Jackson M. Alzari P.M. J. Biol. Chem. 2007; 282: 20705-20714Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). Interestingly, critical residues and their interactions are preserved in PimA and PimB′, strongly supporting conserved catalytic and membrane association mechanisms (23Guerin M.E. Kaur D. Somashekar B.S. Gibbs S. Gest P. Chatterjee D. Brennan P.J. Jackson M. J. Biol. Chem. 2009; 284: 25687-25696Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar).Biosynthesis of PIM5, PIM6, LM, and LAMAc1PIM2 and Ac2PIM2 can be further elongated with additional Manp residues to form higher PIM species (such as Ac1PIM3–Ac1PIM6/Ac2PIM3–Ac2PIM6), LM, and LAM (Fig. 1B). It has been proposed that the third Manp residue of PIM is added to Ac1PIM2 by the nonessential GDP-Manp utilizing α-ManT PimC, identified in the genome of M. tuberculosis CDC1551 (36Kremer L. Gurcha S.S. Bifani P. Hitchen P.G. Baulard A. Morris H.R. Dell A. Brennan P.J. Besra G.S. Biochem. J. 2002; 363: 437-447Crossref PubMed Google Scholar). However, this enzyme is absent from other mycobacterial genomes (e.g. M. smegmatis and M. tuberculosis H37Rv), suggesting the existence of an alternative pathway. Likewise, the α-ManT (PimD) that catalyzes the transfer of the fourth Manp residue onto PI trimannosides remains to be identified. Ac1PIM4/Ac2PIM4 seems to be a branch point intermediate in Ac1PIM6/Ac2PIM6 and LM/LAM biosynthesis. The addition of two α-1,2-linked Manp residues to Ac1PIM4/Ac2PIM4, a combination not found in the mannan backbone of LM and LAM, leads to the formation of the higher order mannosides Ac1PIM6 and Ac2PIM6 (31Morita Y.S. Sena C.B. Waller R.F. Kurokawa K. Sernee M.F. Nakatani F. Haites R.E. Billman-Jacobe H. McConville M.J. Maeda Y. Kinoshita T. J. Biol. Chem. 2006; 281: 25143-25155Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 37Patterson J.H. Waller R.F. Jeevarajah D. Billman-Jacobe H. McConville M.J. Biochem. J. 2003; 372: 77-86Crossref PubMed Scopus (55) Google Scholar, 38Morita Y.S. Patterson J.H. Billman-Jacobe H. McConville M.J. Biochem. J. 2004; 378: 589-597Crossref PubMed Google Scholar). PimE (Rv1159) has been recently identified as an α-1,2-ManT involved in the biosynthesis of higher order PIMs. PimE belongs to the GT-C superfamily of GTs, which comprises integral membrane proteins that use polyprenyl-linked sugars as donors (7Berg S. Kaur D. Jackson M. Brennan P.J. Glycobiology. 2007; 17 (Review): 35-56RCrossref PubMed Scopus (167) Google Scholar, 8Kaur D. Guerin M.E. Skovierová H. Brennan P.J. Jackson M. Adv. Appl. Microbiol. 2009; 69: 23-78Crossref PubMed Scopus (172) Google Scholar, 27Lairson L.L. Henrissat B. Davies G.J. Withers S.G. Annu. Rev. Biochem. 2008; 77: 521-555Crossref PubMed Scopus (1276) Google Scholar, 31Morita Y.S. Sena C.B. Waller R.F. Kurokawa K. Sernee M.F. Nakatani F. Haites R.E. Billman-Jacobe H. McConville M.J. Maeda Y. Kinoshita T. J. Biol. Chem. 2006; 281: 25143-25155Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). A combination of phenotypic characterization of M. tuberculosis and M. smegmatis pimE knock-out mutants and cell-free assays clearly indicated that PimE transfers a Manp residue from polyprenol-phosphate-mannose to Ac1PIM4 to form Ac1PIM5 at the periplasmic face of the plasma membrane (Fig. 1, A and B) (31Morita Y.S. Sena C.B. Waller R.F. Kurokawa K. Sernee M.F. Nakatani F. Haites R.E. Billman-Jacobe H. McConville M.J. Maeda Y. Kinoshita T. J. Biol. Chem. 2006; 281: 25143-25155Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar).4 The α-1,2-ManT responsible for the formation of PIM6 from PIM5 is not yet known.A screening for M. smegmatis transposon mutants with defects in cell envelope synthesis led to the discovery of a mutant harboring an insertion in the putative lipoprotein-encoding gene lpqW (orthologous to Rv1166 of M. tuberculosis H37Rv). On complex media, the mutant formed small colonies that produced much reduced quantities of LAM compared with the wild-type parent strain. This phenotype was unstable, however, as the mutant rapidly evolved to give rise to variants that had restored LAM biosynthesis but failed to produce higher PIMs and accumulated the branch point intermediate Ac1PIM4 (39Kovacevic S. Anderson D. Morita Y.S. Patterson J. Haites R. McMillan B.N. Coppel R. McConville M.J. Billman-Jacobe H. J. Biol. Chem. 2006; 281: 9011-9017Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Consistent with the accumulation of this intermediate, the restoration of LAM synthesis in the lpqW mutant was accounted for by secondary mutations in the pimE gene affecting the extracytoplasmic enzyme activity of this protein (40Crellin P.K. Kovacevic S. Martin K.L. Brammananth R. Morita Y.S. Billman-Jacobe H. McConville M.J. Coppel R.L. J. Bacteriol. 2008; 190: 3690-3699Crossref PubMed Scopus (31) Google Scholar). From these findings, it was proposed that LpqW is required to channel PIM4 into LAM synthesis (Fig. 1B) and that loss of PimE, which results in the accumulation of high levels of Ac1PIM4 in the cells, bypasses the need for LpqW (40Crellin P.K. Kovacevic S. Martin K.L. Brammananth R. Morita Y.S. Billman-Jacobe H. McConville M.J. Coppel R.L. J. Bacteriol. 2008; 190: 3690-3699Crossref PubMed Scopus (31) Google Scholar). The crystal structure of LpqW (41Marland Z. Beddoe T. Zaker-Tabrizi L. Lucet I.S. Brammananth R. Whisstock J.C. Wilce M.C. Coppel R.L. Crellin P.K. Rossjohn J. J. Mol. Biol. 2006; 359: 983-997Crossref PubMed Scopus (20) Google Scholar) revealed an overall fold (Fig. 2C) that resembles those of a family of bacterial substrate-binding proteins (42Tam R. Saier Jr., M.H. Microbiol. Rev. 1993; 57: 320-346Crossref PubMed Google Scholar). A plausible model was suggested in which an electronegative interdomain cavity in LpqW might bind the Ac1PIM4 intermediate (Fig. 2C) to channel it into the LM/LAM biosynthetic pathway, thus controlling the relative abundance of higher PIMs and LM/LAM (Fig. 1B).Compartmentalization of the PIM Biosynthetic Pathway and Translocation of PIMs across the Cell EnvelopeAs evidenced by the nature of the GTs and sugar donors involved and the asymmetrical PIM composition of the inner and outer leaflets of the mycobacterial plasma membrane (43Morita Y.S. Velasquez R. Taig E. Waller R.F. Patterson J.H. Tull D. Williams S.J. Billman-Jacobe H. McConville M.J. J. Biol. Chem. 2005; 280: 21645-21652Abstract Full Text Full Text PDF PubMed" @default.
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