A promiscuous archaeal cardiolipin synthase enables construction of diverse natural and unnatural phospholipids

Exterkate, Marten; Kok, Niels A. W. de; Andringa, Ruben L. H.; Wolbert, Niels H.J.; Minnaard, Adriaan J.; Driessen, Arnold J. M.

doi:10.1016/j.jbc.2021.100691

Cited by 14 publications

(26 citation statements)

References 61 publications

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“…This conservation is reflected by the extreme substrate selectivity of MjPSS for serine. A similar selectivity on the head group of the lipid was observed for the archaeon Methanospirillum hungatei CL synthase, which was able to catalyze both, the synthesis of CL and glycerol-di-archaetidyl-CL 44 . Moreover, it was able to synthetize similar amounts of hybrid glycerol-archaetidyl-phosphatidyl-CL, and that the reaction was reversible, as we also observed for MjPSS (Supplementary Fig.…”

Section: Discussionsupporting

confidence: 61%

Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases

et al. 2021

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Phospholipids are the major components of the membrane in all type of cells and organelles. They also are critical for cell metabolism, signal transduction, the immune system and other critical cell functions. The biosynthesis of phospholipids is a complex multi-step process with high-energy intermediates. Several enzymes in different metabolic pathways are involved in the initial phospholipid synthesis and its subsequent conversion. While the “Kennedy pathway” is the main pathway in mammalian cells, in bacteria and lower eukaryotes the precursor CDP-DAG is used in the de novo pathway by CDP-DAG alcohol O-phosphatidyl transferases to synthetize the basic lipids. Here we present the high-resolution structures of phosphatidyl serine synthase from Methanocaldococcus jannaschii crystallized in four different states. Detailed structural and functional analysis of the different structures allowed us to identify the substrate binding site and show how CDP-DAG, serine and two essential metal ions are bound and oriented relative to each other. In close proximity to the substrate binding site, two anions were identified that appear to be highly important for the reaction. The structural findings were confirmed by functional activity assays and suggest a model for the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases, which synthetize the phospholipids essential for the cells.

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Section: Discussionsupporting

confidence: 61%

Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases

et al. 2021

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“…PLD-type Cls synthesize CL through the reversible condensation of two phosphatidylglycerol moieties, forming CL and releasing a glycerol moiety in the process. In addition to cardiolipin synthase activity, PLD-type Cls have been shown to exhibit typical phospholipase-D activity as well, irreversibly hydrolyzing the headgroup of PG to yield PA and glycerol (Jeucken et al 2018 ; Exterkate et al 2021 ). The second group of Cls belongs to the CAPT family and has been identified in eukaryotes; forming CL by linking CDP-DAG to the terminal hydroxyl group of the glycerol headgroup on PG, releasing a CMP moiety in the process (Schlame and Greenberg 1997 ; Sandoval-Calderón et al 2009 ).…”

Section: Introductionmentioning

confidence: 99%

“…The regions of residues 7–29 and 33–64 in the N-terminal domain of EcClsA contain stretches of hydrophobic residues flanked C-terminally by positively charged residues and are predicted to each form a transmembrane helix. The second hydrophobic region contains a motif of unknown function and is conserved among ClsA of some well-known bacteria and MhCls (Exterkate et al 2021 ) (Fig. 11 d).…”

Section: Introductionmentioning

confidence: 99%

“…This resulted in the synthesis of natural and various non-natural phospholipids in vitro. Furthermore, MhCls was found to be active on bacterial G3P-based ester phospholipids in addition to the archaeal G1P-based ether phospholipids (Exterkate et al 2021 ). Remarkably, the enzyme is capable of generating a hybrid phospholipid species, not before seen in nature, where PG is coupled to AG.…”

Section: Introductionmentioning

confidence: 99%

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The catalytic and structural basis of archaeal glycerophospholipid biosynthesis

Kok

Driessen

2022

Extremophiles

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Archaeal glycerophospholipids are the main constituents of the cytoplasmic membrane in the archaeal domain of life and fundamentally differ in chemical composition compared to bacterial phospholipids. They consist of isoprenyl chains ether-bonded to glycerol-1-phosphate. In contrast, bacterial glycerophospholipids are composed of fatty acyl chains ester-bonded to glycerol-3-phosphate. This largely domain-distinguishing feature has been termed the “lipid-divide”. The chemical composition of archaeal membranes contributes to the ability of archaea to survive and thrive in extreme environments. However, ether-bonded glycerophospholipids are not only limited to extremophiles and found also in mesophilic archaea. Resolving the structural basis of glycerophospholipid biosynthesis is a key objective to provide insights in the early evolution of membrane formation and to deepen our understanding of the molecular basis of extremophilicity. Many of the glycerophospholipid enzymes are either integral membrane proteins or membrane-associated, and hence are intrinsically difficult to study structurally. However, in recent years, the crystal structures of several key enzymes have been solved, while unresolved enzymatic steps in the archaeal glycerophospholipid biosynthetic pathway have been clarified providing further insights in the lipid-divide and the evolution of early life.

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“…Nevertheless, physicochemical properties of membrane glycerophospholipids vary significantly between the domains of organisms. The differences between bacterial/eukaryotic and archaeal lipids are thought to enable Archaea to survive in inhospitable environments ( Oger and Cario, 2013 ) and are the basis of the “lipid divide” ( Koga, 2011 ; Exterkate et al, 2021 ; Sohlenkamp, 2021 ). Comprehensive characterization of the lipidome of archaea and the genetically modified or synthetic organisms ( Villanueva et al, 2020 ; Exterkate et al, 2021 ) may provide us insights into an enigma of microbial evolution assisted by membrane functions ( Villanueva et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

A Novel Approach to Characterize the Lipidome of Marine Archaeon Nitrosopumilus maritimus by Ion Mobility Mass Spectrometry

Law

Tao

et al. 2021

Front. Microbiol.

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Archaea are differentiated from the other two domains of life by their biomolecular characteristics. One such characteristic is the unique structure and composition of their lipids. Characterization of the whole set of lipids in a biological system (the lipidome) remains technologically challenging. This is because the lipidome is innately complex, and not all lipid species are extractable, separable, or ionizable by a single analytical method. Furthermore, lipids are structurally and chemically diverse. Many lipids are isobaric or isomeric and often indistinguishable by the measurement of mass or even their fragmentation spectra. Here we developed a novel analytical protocol based on liquid chromatography ion mobility mass spectrometry to enhance the coverage of the lipidome and characterize the conformations of archaeal lipids by their collision cross-sections (CCSs). The measurements of ion mobility revealed the gas-phase ion chemistry of representative archaeal lipids and provided further insights into their attributions to the adaptability of archaea to environmental stresses. A comprehensive characterization of the lipidome of mesophilic marine thaumarchaeon, Nitrosopumilus maritimus (strain SCM1) revealed potentially an unreported phosphate- and sulfate-containing lipid candidate by negative ionization analysis. It was the first time that experimentally derived CCS values of archaeal lipids were reported. Discrimination of crenarchaeol and its proposed stereoisomer was, however, not achieved with the resolving power of the SYNAPT G2 ion mobility system, and a high-resolution ion mobility system may be required for future work. Structural and spectral libraries of archaeal lipids were constructed in non-vendor-specific formats and are being made available to the community to promote research of Archaea by lipidomics.

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A promiscuous archaeal cardiolipin synthase enables construction of diverse natural and unnatural phospholipids

Cited by 14 publications

References 61 publications

Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases

Crystal structures of phosphatidyl serine synthase PSS reveal the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases

The catalytic and structural basis of archaeal glycerophospholipid biosynthesis

A Novel Approach to Characterize the Lipidome of Marine Archaeon Nitrosopumilus maritimus by Ion Mobility Mass Spectrometry

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