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Small molecule hijacking brings together biosynthetic pathways

A recent paper from Dr Bali, working in Professor Ferguson’s laboratory, in collaboration with a group at the University of Kent in Canterbury, sheds light on new biosynthetic pathways that produce pigments which play a key role in many organisms. Heme, the best-known of these pigments, gives blood its colour and allows red blood cells to carry oxygen round the body.

Model of Heme B

Model of Heme B
(Click to enlarge)

The group’s BBSRC-supported research, published in the Proceedings of the National Academy of Sciences (1), has shown how a set of novel enzymes unexpectedly hijacks a compound called siroheme - involved in a process that assimilates nitrite and sulphite into biologically important compounds – for use in these pathways.

The discovery of a connection between these two different processes provides insight into how biochemical pathways evolve and become more complex.

Heme is an example of a prosthetic group – a chemical compound that, when attached to a protein, can carry out a specific role. In the case of blood this protein is haemoglobin. Heme and its associated proteins have many roles in cells including in respiration and photosynthesis.

Heme contains an atom of iron surrounded by a cyclic molecule known as a porphyrin which binds to the iron via its four nitrogen atoms. Cells have enzymes that catalyse a series of reactions that generate porphyrins from much smaller non-cyclic precursors. Over the years, researchers have identified these enzymes and the reactions they catalyse in animals, plants and many species of bacteria.

There are structural variations on the ‘standard’ heme molecule that function as prosthetic groups for other biologically important proteins and enzymes. For example, a molecule called d1 heme occurs in a key enzyme of the nitrogen cycle in bacteria (cytochrome cd1 nitrite reductase) that has been studied in Professor Ferguson’s laboratory for some years. Attempts to understand how d1 heme is made have been unsuccessful until recently.

With the widespread sequencing of microbial genomes, researchers have found that some species of bacteria and archaea (a unique type of single-celled organism) lack the genes coding for the enzymes known to catalyse heme synthesis in most types of cells. Curiously, these organisms carry genes very similar to those implicated in d1 heme biosynthesis, even though the organisms themselves do not contain the gene coding for cytochrome cd1 nitrite reductase.

To understand what these genes are doing, Dr Bali expressed them in E.coli. She discovered that some of them were part of a biosynthetic pathway involving another prosthetic group called siroheme. The appearance of siroheme as an intermediate in the synthesis of d1 heme was unexpected given what was known about the pathways to heme production.

Figure showing the newly discovered pathway to heme and d<sub>1</sub> heme synthesis that involves siroheme as an intermediate

Figure showing the newly discovered pathway to heme and d1 heme synthesis that involves siroheme as an intermediate (Click to enlarge)

Once this pathway had been revealed, an entirely novel route to heme synthesis fell into place. This was experimentally demonstrated in collaboration with colleagues at the University of Kent and also at Portugal’s Instituto de Tecnologia Química e Biológica. More work to fill in the missing steps in the d1 heme synthesis pathway from siroheme is currently underway.

The research raises an interesting evolutionary question about siroheme. Did siroheme first evolve to be the precursor on the biosynthetic pathways for making heme and d1 heme, and then find itself hijacked for use in the nitrite and sulphite assimilatory pathway? Or could it have been the other way round?

There are clues that reduction of nitrite by cytochrome cd1 may have preceded the appearance of oxygen, whereas assimilation of sulphite and nitrite may have occurred only after oxygen appeared on earth. This suggests that d1 heme came before siroheme.

Another unanswered question raised by these studies is to why certain groups of bacteria and archaea use this newly discovered pathway of heme synthesis. Not all archaeal species possess heme. This implies that it is not necessarily the ‘ancient’ route for heme synthesis and that it may have been acquired by lateral gene transfer from species of bacteria, such as the sulfate-reducing bacteria, that possess the pathway involving siroheme.

Intriguingly, in other work supported by the BBSRC, the Ferguson laboratory has found that archaea and sulfate-reducing bacteria also share a common system for attaching heme to proteins to give c-type cytochromes. As this type of cytochrome is not common in archaea, this suggests that gene transfer could have occurred here too.


  1. ‘Molecular hijacking of siroheme for the synthesis of heme and d1 heme’. Shilpa Bali, Andrew D. Lawrence, Susana A. Lobo, Lígia M. Saraiva, Bernard T. Golding, David J. Palmer, Mark J. Howard, Stuart J. Ferguson and Martin J. Warren. PNAS, 108, 18260-18265 (2011).



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