Methylotrophy is a metabolic capability possessed by microorganisms that allows them to build biomass and to obtain energy from organic substrates containing no carbon-carbon bonds (C1 compounds, such as methane, methanol, etc.). This phenomenon in microbial physiology has been a subject of study for over 100 years, elucidating a set of well-defined enzymatic systems and pathways enabling this capability. The knowledge gained from the early genetic and genomic approaches to understanding methylotrophy pointed towards the existence of alternative enzymes/pathways for the specific metabolic goals. Different combinations of these systems in different organisms suggested that methylotrophy must be modular in its nature. More recent insights from genomic analyses, including the genomes representing novel types of methylotrophs, seem to reinforce this notion. This review integrates the new findings with the previously developed concept of modularity of methylotrophy.

Modularity of methylotrophy, revisited.

Methylotrophy is defined as the ability to “grow at the expense of reduced carbon compounds containing one or more carbon atoms but containing no carbon-carbon bonds” (3). It is an intriguing example of microbial metabolic agility, with the use of a class of chemicals disregarded by the majority of organisms. Even though the ability to grow methylotrophically was first discovered in the early 1900s (cited in reference 3), it was not until the 1960s to 1970s that an understanding of the biochemical nature of this capability started to emerge. Fascination with methylotrophy in those years was fueled by the commercial interest in single-cell protein production, and as a result, the specific details of the biochemistry of methylotrophy began to be revealed. Enzymes for the primary oxidation of C1 substrates such as methanol dehydrogenase and methylamine dehydrogenase were characterized, and distinct modes of C1 assimilation, such as the ribulose monophosphate cycle and the serine cycle were discovered. The biochemical processes involved in methylotrophy that were known by 1982 are described in detail in the now classic book Biochemistry of Methylotrophs by Christopher Anthony (3). In the 20 years following the publication of Biochemistry of Methylotrophs, a few additional methylotrophy biochemical pathways have been discovered, such as the pathway for C1 transfer linked to methanopterin and methanofuran, which solved the long-standing mystery of formaldehyde oxidation in many methylotrophs (15, 53), and novel pathways for primary C1 oxidation, such as the pathways for degradation of chlorinated methanes and methanesulfonic acid (21, 50).

The knowledge concerning the biochemistry and physiology of methylotrophic organisms accumulated over the past three decades suggests a new framework for understanding methylotrophy as a novel metabolic mode. In this framework, methylotrophy is envisioned as a set of specific metabolic functional modules, with different combinations of such modules being present in different methylotrophs (Fig. ​(Fig.11 for the methylotrophic metabolic modules in Methylobacterium extorquens AM1). However, until recently, a number of important details of these modules were missing, and so the picture remained incomplete. The availability of two unfinished genome sequences for the important model organisms M. extorquens AM1 (http://www.integratedgenomics.com/genomereleases.html#list6)and Methylococcus capsulatus Bath (http://tigrblast.tigr.org/ufmg/) is transforming our understanding of methylotrophy. Annotation of these two genomes combined with functional analysis will delineate the set of genes and functions that is both sufficient and necessary to define a methylotroph. Expanding genomic analyses to include other groups of methylotrophs will in turn provide clues to the origins of methylotrophy and the evolution of various methylotrophic pathways. In this publication, we summarize the existing knowledge of the genes involved in methylotrophic pathways in M. extorquens AM1, analyze its yet unfinished genome with respect to location and clustering of methylotrophy genes, and present a comprehensive list of methylotrophy genes and enzymes known at this time in M. extorquens AM1 (Table ​(Table11).



FIG. 1.

Methylotrophy metabolic modules in M. extorquens AM1. Known genes are in italic. For simplicity, redox reactions in the assimilatory pathways are not indicated. For details, refer to the references given in Table ​Table11.





TABLE 1.

Methylotrophy genes in M. extorquens AM1

Methylotrophy in Methylobacterium extorquens AM1 from a genomic point of view.

The phyllosphere, which lato sensu consists in the aerial parts of plants, and therefore primarily, in the set of photosynthetic leaves, is one of the most prevalent microbial habitats on Earth. Phyllospheric microbiota are related to original and specific processes that govern the interface between plants, microorganisms and the atmosphere. Recent –omics studies have opened fascinating opportunities for characterising the spatio-temporal structure of phyllosphere microbial communities in relation with structural, functional and ecological properties of host plants, and with physico-chemical properties of the environment, such as climate dynamics and trace gas composition of the surrounding atmosphere. This review will analyse recent advances, especially those resulting from environmental genomics, and how this novel knowledge has revealed the extent of the ecosystemic impact of the phyllosphere at the interface between plants and atmosphere. Highlights • The phyllosphere is one of the most prevalent microbial habitats on Earth • Phyllospheric microbiota colonize extreme, stressful and changing environments • Plants, phyllospheric microbiota and the atmosphere present a dynamic continuum • Phyllospheric microbiota interact with the dynamics of volatile organic compounds and atmospheric trace gases

/pdf/pivotal-roles-of-phyllosphere-microorganisms-at-the-qgv43pz7f3.pdf

Pivotal roles of phyllosphere microorganisms at the interface between plant functioning and atmospheric trace gas dynamics.

The phylum Verrucomicrobia is a widespread but poorly characterized bacterial clade. Although cultivation-independent approaches detect representatives of this phylum in a wide range of environments, including soils, seawater, hot springs and human gastrointestinal tract, only few have been isolated in pure culture. We have recently reported cultivation and initial characterization of an extremely acidophilic methanotrophic member of the Verrucomicrobia, strain V4, isolated from the Hell's Gate geothermal area in New Zealand. Similar organisms were independently isolated from geothermal systems in Italy and Russia. We report the complete genome sequence of strain V4, the first one from a representative of the Verrucomicrobia. Isolate V4, initially named "Methylokorus infernorum" (and recently renamed Methylacidiphilum infernorum) is an autotrophic bacterium with a streamlined genome of ~2.3 Mbp that encodes simple signal transduction pathways and has a limited potential for regulation of gene expression. Central metabolism of M. infernorum was reconstructed almost completely and revealed highly interconnected pathways of autotrophic central metabolism and modifications of C1-utilization pathways compared to other known methylotrophs. The M. infernorum genome does not encode tubulin, which was previously discovered in bacteria of the genus Prosthecobacter, or close homologs of any other signature eukaryotic proteins. Phylogenetic analysis of ribosomal proteins and RNA polymerase subunits unequivocally supports grouping Planctomycetes, Verrucomicrobia and Chlamydiae into a single clade, the PVC superphylum, despite dramatically different gene content in members of these three groups. Comparative-genomic analysis suggests that evolution of the M. infernorum lineage involved extensive horizontal gene exchange with a variety of bacteria. The genome of M. infernorum shows apparent adaptations for existence under extremely acidic conditions including a major upward shift in the isoelectric points of proteins. The results of genome analysis of M. infernorum support the monophyly of the PVC superphylum. M. infernorum possesses a streamlined genome but seems to have acquired numerous genes including those for enzymes of methylotrophic pathways via horizontal gene transfer, in particular, from Proteobacteria. This article was reviewed by John A. Fuerst, Ludmila Chistoserdova, and Radhey S. Gupta.

/pdf/complete-genome-sequence-of-the-extremely-acidophilic-1xch5adm2a.pdf

Complete genome sequence of the extremely acidophilic methanotroph isolate V4, Methylacidiphilum infernorum, a representative of the bacterial phylum Verrucomicrobia.

Methylotrophic bacteria can grow on a number of substrates as energy source with only one carbon atom, such as methanol, methane, methylamine, and dichloromethane These compounds are metabolized via the cytotoxin formaldehyde The formaldehyde consumption pathways, especially the pathways for the oxidation of formaldehyde to CO2 for energy metabolism, are a central and critical part of the metabolism of these aerobic bacteria Principally, two main types of pathways for the conversion of formaldehyde to CO2 have been described: (1) a cyclic pathway initiated by the condensation of formaldehyde with ribulose monophosphate, and (2) distinct linear pathways that involve a dye-linked formaldehyde dehydrogenase or C1 unit conversion bound to the cofactors tetrahydrofolate (H4F), tetrahydromethanopterin (H4MPT), glutathione (GSH), or mycothiol (MySH) The pathways involving the four cofactors have in common the following sequence of events: the spontaneous or enzyme-catalyzed condensation of formaldehyde and the respective C1 carrier, the oxidation of the cofactor-bound C1 unit and its conversion to formate, and the oxidation of formate to CO2 However, the H4MPT pathway is more complex and involves intermediates that were previously known solely from the energy metabolism of methanogenic archaea The occurrence of the different formaldehyde oxidation pathways is not uniform among different methylotrophic bacteria The pathways are in part also used by other organisms to provide C1 units for biosynthetic reactions (eg, H4F-dependent enzymes) or detoxification of formaldehyde (eg, GSH-dependent enzymes)

Cofactor-dependent pathways of formaldehyde oxidation in methylotrophic bacteria.

Methylobacterium sp. strain CM4, an aerobic methylotrophic α-proteobacterium, is able to grow with chloromethane as a carbon and energy source. Mutants of this strain that still grew with methanol, methylamine, or formate, but were unable to grow with chloromethane, were previously obtained by miniTn5 mutagenesis. The transposon insertion sites in six of these mutants mapped to two distinct DNA fragments. The sequences of these fragments, which extended over more than 17 kb, were determined. Sequence analysis, mutant properties, and measurements of enzyme activity in cell-free extracts allowed the definition of a multistep pathway for the conversion of chloromethane to formate. The methyl group of chloromethane is first transferred by the protein CmuA (cmu: chloromethane utilization) to a corrinoid protein, from where it is transferred to H4folate by CmuB. Both CmuA and CmuB display sequence similarity to methyltransferases of methanogenic archaea. In its C-terminal part, CmuA is also very similar to corrinoid-binding proteins, indicating that it is a bifunctional protein consisting of two domains that are expressed as separate polypeptides in methyl transfer systems of methanogens. The methyl group derived from chloromethane is then processed by means of pterine-linked intermediates to formate by a pathway that appears to be distinct from those already described in Methylobacterium. Remarkable features of this pathway for the catabolism of chloromethane thus include the involvement of a corrinoid-dependent methyltransferase system for dehalogenation in an aerobe and a set of enzymes specifically involved in funneling the C1 moiety derived from chloromethane into central metabolism.

https://www.pnas.org/content/pnas/96/8/4615.full.pdf

A corrinoid-dependent catabolic pathway for growth of a Methylobacterium strain with chloromethane

The metabolism of dichloromethane by Dehalobacterium formicoaceticum in cell suspensions and crude cell extracts was investigated. The organism is a strictly anaerobic gram-positive bacterium that utilizes exclusively dichloromethane as a growth substrate and ferments this compound to formate and acetate in a molar ratio of 2:1. When [C]dichloromethane was degraded by cell suspensions, formate, the methyl group of acetate, and minor amounts of methanol were labeled, but there was no nuclear magnetic resonance signal corresponding to the carboxyl group of acetate. This finding and previously established carbon and electron balances suggested that dichloromethane was converted to methylene tetrahydrofolate, of which two-thirds was oxidized to formate while one-third gave rise to acetate by incorporation of CO(2) from the medium in the acetyl coenzyme A synthase reaction. When crude desalted extracts were incubated in the presence of dichloromethane, tetrahydrofolate, ATP, methyl viologen, and molecular hydrogen, dichloromethane and tetrahydrofolate were consumed, with the concomitant formation of stoichiometric amounts of methylene tetrahydrofolate. The in vitro transfer of the methylene group of dichloromethane onto tetrahydrofolate required substoichiometric amounts of ATP. The reaction was inhibited in a light-reversible fashion by 20 muM propyl iodide, thus suggesting involvement of a Co(I) corrinoid in the anoxic dehalogenation of dichloromethane. D. formicoaceticum exhibited normal growth with 0.8 mM sodium in the medium, and crude extracts contained ATPase activity that was partially inhibited by N,N'-dicyclohexylcarbodiimide and azide. During growth with dichloromethane, the organism thus may conserve energy not only by substrate-level phosphorylation but also by a chemiosmotic mechanism involving a sodium-independent F(0)F(1)-type ATP synthase.

Metabolism of Dichloromethane by the Strict Anaerobe Dehalobacterium formicoaceticum.

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A corrinoid-dependent catabolic pathway for growth of a Methylobacterium strain with chloromethane

Metabolism of Dichloromethane by the Strict Anaerobe Dehalobacterium formicoaceticum.