Bridging the divide: bacteria synthesizing archaeal membrane lipids

Laura Villanueva, F. A. Bastiaan von Meijenfeldt, Alexander B. Westbye, Ellen C. Hopmans, Bas E. Dutilh, Jaap S. Sinninghe Damste

Preprint posted on 19 October 2018


Extensive transfer of membrane lipid biosynthetic genes between Archaea and Bacteria

Gareth A. Coleman, Richard D. Pancost, Tom A. Williams

Preprint posted on 2 May 2018

Straddling the lipid divide: evidence that archaea and bacteria have exchanged lipid biosynthesis genes in the past, and that a present-day Black Sea bacterium might possess a mixed membrane

Selected by Dey Lab

[Note added 2018/10/26: Coleman et al. released an updated version of their preprint on the 25th of October, which includes additional analyses and updated figures. The broad conclusions of the manuscript remain unchanged. You can find the updated preprint here. Figure 1 is taken from the updated preprint (Coleman et al. 2018b).



The genomes of bacteria and archaea, the two primary domains of life, provide strong support for a conserved core of universal genes and the idea that there was once a single primordial cellular lineage- the Last Universal Common Ancestor (LUCA)1. Yet, extant archaea and bacteria differ in striking ways, including a critical difference in membrane chemistry2 (Figure 1).  The isoprenoid ether-linked glycerol-1-phosphate (G1P) lipids of archaea and the acyl ester-linked G3P lipids of bacteria, at first glance, could not appear more different- from the unique enzyme cascades needed to produce them down to the chirality of the backbone.


Figure 1, reproduced in full from Coleman et al. 2018b under a Creative Commons CC-BY 4.0 international license. a) The canonical ether/ester biosynthetic pathways in Archaea and Bacteria and how they relate to glycerol metabolism. Based on Figure 1 from Villanueva et al (2016). Archaeal pathways in blue and yellow (blue=heterotrophic Archaea, yellow=autotrophic Archaea), bacterial pathway in red. Hypothetical biosynthetic pathway, as suggested by Villanueva et al. (2016), in dashed lines. b) Composition of bacterial and archaeal phospholipids. In Archaea, G1P is synthesised from dihydroxyacetone phosphate (DHAP) using the enzymes glycerol-1-phosphate dehydrogenase (G1PDH). The first and second isoprenoid chains (GGGPs) are added by geranylgeranylglyceryl synthase (GGGPS) and digeranylgeranylglyceryl synthase (DGGGPS) respectively. In Bacteria, G3P is synthesised by glycerol-3-phosphate dehydrogenase (G3PDH) from DHAP. There are two forms of this enzyme, encoded by the gpsA and glp genes respectively. G3P may also be produced from glycerol by glycerol kinase (glpK). In certain Bacteria, such as Gammaproteobacteria, the first fatty-acid chain is added by a version of glycerol-3-phosphate acyltransferase encoded by the PlsB gene. Other Bacteria, including most gram positive bacteria, use a system which includes another glycerol-3-phosphate acyltransferase encoded by PlsY, in conjunction with an enzyme encoded by PlsX (Yao and Rock 2013; Parsons and Rock 2013). The second fattyacid chain is attached by 1-acylglycerol-3-phosphate O-acyltransferase, encode by PlsC.


The consequences of this apparent “lipid divide”3 for theories of cellular evolution are momentous. For example, did LUCA even have a membrane, or was it an acellular entity occupying a porous substrate4? Did early eukaryotes, whose extant representatives possess bacterial-type lipid chemistry, eliminate the membrane lipids of their likely archaeal ancestor, and did they necessarily transition through a heterochiral intermediate5?

 As it turns out, though, a growing body of experimental and genomic evidence suggests that the lipid divide might be narrower than once thought, setting the stage for the two preprints highlighted here. Notably, Bacillus subtilis has been shown to make both bacterial and archaeal lipids6; earlier this year, an engineered E. coli strain equipped with a mix of the right bacterial and archaeal enzymes was shown to stably maintain a mixed heterochiral membrane7.

Major findings 

Coleman et al. investigate the distribution and phylogeny of the core phospholipid biosynthesis enzymes outlined in Figure 1 across bacteria and archaea. They find that the archaeal enzymes are widely prevalent in bacterial lineages. With all 3 core archaeal enzymes present, some species of the Firmicutes, Actinobacteria and Fibrobacteres lineages probably make G1P phospholipids. The story is a bit less clear for species belonging to the other two-thirds of the FBC group (Fibrobacteres, Bacteroidetes and Chlorobi) which have GGGPS and DGGGPS orthologs but no G1PDH.  Examining transfers in the other direction, the bacterial enzymes appeared more sporadically in the archaeal genomes, with no phylum containing homologs of all the genes and more than half containing none.

Coleman et al. go on to construct rooted Bayesian single-gene phylogenies for their set of core biosynthetic genes. Using these phylogenies, they suggest that G1PDH was either present in LUCA or transferred very early from stem archaea to bacterial groups or the bacterial stem; GGGPS probably duplicated once pre-LUCA, with evidence of two distinct paralogs; DGGGPS was either present in LUCA or transferred to bacteria multiple times from the archaea. In contrast, the roots for the bacterial enzyme trees lie (albeit weakly) within the bacterial domain, with concomitant evidence of multiple recent transfers to archaea. Thus, a tentative yet striking conclusion from the study is that the archaeal synthesis pathway might be older than the bacterial one.

It is worth noting, as the authors do point out, that transfer timing-related conclusions must necessarily be treated with caution given the uncertainty in placing the roots for trees spanning such large evolutionary distances. For those interested, I strongly recommend a deep dive into the extensive discussion of rooting strategies detailed in the manuscript.

Villanueva et al. describe the discovery and metagenomic assembly of 4 novel, near-complete Candidatus Cloacimonetes genomes (belonging to the FBC/FCB group) sampled from the deep waters of the Black Sea. First, they find genes consistent with the biosynthesis of canonical bacterial membranes, including G3P synthesis and esterification. They also identify bona-fide GGGPS and DGGGP synthase homologs, proximally located in the genome and with high homology to their archaeal counterparts. Importantly, they also identify matching gene transcripts in the Black Sea samples.

When expressed in E. coli, a recombinant Ca. Cloacimonetes GGGPS catalyzes the formation of GGGP from GGPP. Co-expressing GGGPS and DGGGP in E. coli (engineered to produce the right precursors) leads to the production of phosphatidylglycerol archaeol, consistent with the hypothesis that these enzymes could be producing bona fide archaeal-type lipids in vivo.

Echoing the findings of Coleman et al., Villanueva et al. point out that their metagenomic assemblies are missing the first enzyme in the cascade- G1PDH (Figure 1)- as well as its bacterial homolog. This is not necessarily a problem, as E. coli engineered to make heterochiral membranes can produce G1P lipids without either enzyme7, suggesting that bacteria possess an alternative G1P synthesis pathway. It remains a formal possibility, however, that the Ca. Cloacimonetes genes are actually making G3P lipids, or are involved in a catabolic rather than anabolic pathway.



The studies highlighted here add to the growing consensus that archaea and bacteria have the capacity to mix and match their phospholipid biosynthesis pathways, much like many other facets of their metabolism and cell biology.

What does this mean for models of cellular evolution? Models analysing the LUCA can no longer rely on the existence of a strict lipid divide as proof that the first cells had no membrane, and must now contend with the possibility that the archaeal lipid biosynthesis pathway might be significantly older than the bacterial one.

The challenge for models of eukaryogenesis is twofold. First, the next generation of models must include the possibility that the archaeal host and/or bacterial endosymbiont already possessed mixed or heterochiral membranes. There is some evidence that genomes of the Asgard clade of archaea, closest known archaeal relatives to eukaryotes, encode components of both bacterial-type and archaeal-type lipid biosynthesis pathways8. Second, if mixed membranes are stable, the ensuing loss of heterochirality in the proto-eukaryote will require an additional explanation (based on environmental factors, for example).



  1. Weiss, M. C. et al. The physiology and habitat of the last universal common ancestor. Nat. Microbiol. 1, 16116 (2016).
  2. Lombard, J., López-García, P. & Moreira, D. The early evolution of lipid membranes and the three domains of life. Nat. Rev. Microbiol. 10, 507–515 (2012).
  3. Koga, Y. Early Evolution of Membrane Lipids: How did the Lipid Divide Occur? J. Mol. Evol. 72, 274–282 (2011).
  4. Martin, W. & Russell, M. J. On the origins of cells: a hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. Philos. Trans. R. Soc. B Biol. Sci. 358, 59–85 (2003).
  5. Baum, D. A. A comparison of autogenous theories for the origin of eukaryotic cells. Am. J. Bot. 102, 1954–65 (2015).
  6. Guldan, H., Matysik, F.-M., Bocola, M., Sterner, R. & Babinger, P. Functional Assignment of an Enzyme that Catalyzes the Synthesis of an Archaea-Type Ether Lipid in Bacteria. Angew. Chemie Int. Ed. 50, 8188–8191 (2011).
  7. Caforio, A. et al. Converting Escherichia coli into an archaebacterium with a hybrid heterochiral membrane. Proc. Natl. Acad. Sci. U. S. A. 115, 3704–3709 (2018).
  8. Villanueva, L., Schouten, S. & Damsté, J. S. S. Phylogenomic analysis of lipid biosynthetic genes of Archaea shed light on the ‘lipid divide’. Environ. Microbiol. 19, 54–69 (2017).


Tags: cellular evolution, heterochiral membranes, leca, lipid divide, luca

Posted on: 21 October 2018 , updated on: 26 October 2018


(No Ratings Yet)

Authors' comment

Gareth Coleman and Tom Williams shared about Extensive transfer of membrane lipid biosynthetic genes between Archaea and Bacteria

Thanks for the interest in our work. One thing that seems quite clear now is that there’s a growing body of evidence (our trees, but also a number of important previous studies using outgroup rooting) that some of the genes involved in making membranes are shared between Bacteria and Archaea. It hasn’t been clear what these shared genes might be doing when they are found in the “other” domain, which is why the new work by Villanueva et al. is so interesting: it shows that in Cloacimonetes, the archaeal genes can support the production of archaeal-type membrane phospholipids, at least when heterologously expressed in E. coli.

One finding from our work that could be of general interest is that outgroup-free rooting can be a viable (perhaps complementary) approach to traditional outgroup rooting, especially when the branch leading to the outgroup is long. There are certainly lots of other interesting questions in early evolution where being able to root gene trees would be useful.

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.


List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.


List by Nadja Hümpfer et al.


The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!


List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.


List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020


List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.


List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria


List by Dey Lab, Samantha Seah


Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.


List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20


List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.


List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome


List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)


List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019


List by Dey Lab


Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.


List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.


List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.


List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019


List by Dey Lab


This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.


List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA


List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.


List by Dey Lab, Amanda Haage

Also in the evolutionary biology category: