Methylotroph

Methylotrophs are a diverse group of microorganisms that can use reduced one-carbon compounds, such as methanol or methane, as the carbon source for their growth; and multi-carbon compounds that contain no carbon-carbon bonds, such as dimethyl ether and dimethylamine. This group of microorganisms also includes those capable of assimilating reduced one-carbon compounds by way of carbon dioxide using the ribulose bisphosphate pathway. These organisms should not be confused with methanogens which on the contrary produce methane as a by-product from various one-carbon compounds such as carbon dioxide. Some methylotrophs can degrade the greenhouse gas methane, and in this case they are called methanotrophs. The methanotroph Methylococcus capsulatus is used to degrade methane and other pollutants. The abundance, purity, and low price of methanol compared to commonly used sugars make methylotrophs competent organisms for production of amino acids, vitamins, recombinant proteins, single-cell proteins, co-enzymes and cytochromes.

Metabolism

The key intermediate behind methylotrophic metabolism is formaldehyde which can be diverted to either catabolism or anabolism. Methylotrophs arrive at formaldehyde through oxidation of methanol and/or methane. Methane oxidation requires the enzyme methane monooxygenase (MMO). Methylotrophs with this enzyme are given the name methanotrophs. The oxidation of methane (or methanol) can be assimilatory or dissimilatory in nature (See Figure 1). If dissimilatory, the formaldehyde product will be oxidized completely into ${\ce {CO2}}$ to produce reductant and energy. If assimilatory, formaldehyde is used to synthesize a 3-Carbon (${\ce {C3}}$) compound used for the production of biomass. Many methylotrophs may use multi-carbon compounds for anabolism, limiting their use of formaldehyde to dissimilatory processes, while methanotrophs are generally limited to only ${\textstyle {\ce {C1}}}$metabolism.

Compounds known to support methylotrophic metabolism

Single Carbon Compounds	Chemical Formula	Multi-Carbon Compounds	Chemical Formula
Carbon monoxide	${\ce {CO}}$	Dimethyl ether	${\ce {(CH3)2O}}$
Formaldehyde	${\ce {CH2O}}$	Dimethylamine	${\ce {(CH3)2NH}}$
Formamide	${\ce {HCONH2}}$	Dimethyl sulfide	${\ce {(CH3)2S}}$
Formic acid	${\ce {HCOOH}}$	Tetramethylammonium	${\ce {(CH3)4N+}}$
Methane	${\ce {CH4}}$	Trimethylamine	${\ce {(CH3)3N}}$
Methanol	${\ce {CH3OH}}$	Trimethylamine N-oxide	${\ce {(CH3)3NO}}$
Methylamine	${\ce {CH3NH2}}$	Trimethylsuphonium	${\ce {(CH3)3S+}}$
Methyl halide	${\ce {CH3X}}$

File:Common methylotrophic metabolic pathways.jpg

General steps of methylotrophic metabolism displaying 4 known assimilatory methylotrophic pathways. The general catabolic pathway is also shown. Q denotes a membrane-bound quinone. Methane monooxygenase (MMO) and Formate dehydrogenase (FDH) may be membrane-associated or cytoplasmic while Methanol dehydrogenase (MDH) and Formaldehyde dehydrogenase (FALDH) are always membrane-associated.

Catabolism

Methylotrophs use the electron transport chain to conserve the energy from the oxidation steps. For methanotrophs, an activation step is required to make chemically-stable methane amenable for further degradation. This oxidation to methanol is catalyzed by MMO which incorporates 1 oxygen atom into methane and reduces the other oxygen atom to water, which requires 2 equivalents of reducing power. Methanol is then oxidized to formaldehyde through the action of either methanol dehydrogenase (MDH) in bacteria or a non-specific alcohol oxidase in yeast. Electrons from methanol oxidation are passed to a membrane-associated quinone of the electron transport chain to produce ${\ce {ATP}}$.

In dissimilatory processes, formaldehyde is completely oxidized to ${\ce {CO2}}$ and released. Formaldehyde is oxidized to formate via the action of Formaldehyde dehydrogenase (FALDH) which directly provide electrons to a membrane associated quinone of the electron transport chain, usually cytochrome b or c. In the case of ${\ce {NAD+}}$ associated dehydrogenases, ${\ce {NADH}}$ is produced. Formate is oxidized to ${\ce {CO2}}$ by cytoplasmic or membrane-bound Formate dehydrogenase (FDH) which produces ${\ce {NADH}}$. 

Anabolism

The main metabolic challenge for methylotrophs is the assimilation of single carbon units into biomass. Through de novo synthesis, Methylotrophs must form carbon-carbon bonds with each 1-Carbon (${\ce {C1}}$) molecule. This is an energy intensive process which facultative methylotrophs avoid by using a range of larger organic compounds. However, obligate methylotrophs must assimilate ${\ce {C1}}$ molecules. There are four distinct assimilation pathways with the common theme of generating one ${\ce {C3}}$ molecule . Bacteria use three of these pathways while Fungi use one. All four pathways use multi-carbon intermediates to incorporate the 3 ${\ce {C1}}$ molecules into, then perform a cleavage step which creates a new ${\ce {C3}}$ molecule for biomass. The remaining intermediates are rearranged to regenerate the original multi-carbon intermediates.

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