06:52am Tuesday 22 October 2019

Discovered: the ‘missing link’ in biological pigment biosynthesis

The finding, which will see textbooks on the origins of biochemical pathways rewritten, could have important implications for the design of useful new synthetic biochemicals.

Most famous for giving blood its red colour, haem – a component of haemoglobin along with the globin protein – allows red blood cells to carry oxygen around our bodies. Molecules attached to proteins in this way are called ‘prosthetic groups’: like prosthetic limbs for amputees, they help a protein to function. Haem-containing proteins have a diverse range of biological functions from oxygen transport to lignin degradation.

The production of haem itself (an iron atom contained within an organic ring-shaped structure) has been well documented and follows a common pathway in a wide range of organisms, from man to most bacteria. Now researchers at the Universities of Oxford and Kent have shown, for the first time, that haem can also be made via a novel branch to this pathway that involves a related molecule called sirohaem – a discovery that Professor Martin Warren from the University of Kent has described as being similar in importance and scale to the ‘transformation of the first electronic calculators into the modern mobile phone’.

A glimpse into the past?

The study looked at haem biosynthesis in microorganisms that live in oxygen-free environments (sulphate-reducing and denitrifying bacteria and some Archaea). Using state-of-the-art anaerobic facilities at the University of Kent’s School of Biosciences, the team uncovered some really unusual and unexpected biochemical reactions. Highly sensitive nuclear magnetic resonance (NMR) spectroscopy equipment within the School allowed the structure of new intermediates on the pathway to be determined.

Copyright: iStockphoto Thinkstock 2011

Copyright: iStockphoto Thinkstock 2011

At a molecular level, the team showed that, in Archea, sirohaem is hijacked and brought into the haem biosynthesis pathway. In molecular and cellular biochemistry this is a very rare example of where one prosthetic group is cannibalised for the synthesis of another. They also showed that sirohaem is converted into a specialised prosthetic group that functions in the biological nitrogen cycle. Before this work the link between the ‘missing’ pathway to haem and the route to this specialised molecule had not been envisaged.

“These findings define an important additional role for sirohaem, which was previously only thought to act as a prosthetic group for enzymes that metabolise sulphite and nitrite,” explains Professor Stuart Ferguson from the University of Oxford.

According to Ferguson, the discovery of this new pathway raises some interesting questions about how haem biosynthesis has evolved:

“Our findings suggest an ancestral role for sirohaem before the emergence of an oxygen-rich atmosphere because the specialised prosthetic group may have been functioning earlier in evolution,” Ferguson explains.

Overall, the results suggest an unsuspected evolutionary relationship between key enzymes in the nitrogen cycle, those that metabolise nitrite for the production of ATP in the absence of oxygen (dissimilatory nitrite reductases with the specialised prosthetic group) and those that metabolise nitrite as a source of nitrogen for the biosynthesis of other compounds (assimilatory nitrite reductases with sirohaem), which might have emerged as oxidised nitrogen became more abundant.

Professor Warren, Head of the School of Biosciences at Kent, said, “This is a very important piece of basic science that will undoubtedly find its way into major text books over the next few years as it offers an explanation as to how biochemical pathways evolve and become more complex.

“Moreover, we have learnt some new concepts about how chemistry can be used to change the shape and the character of larger molecules, which can then be applied for the development of new compounds; for instance, in the pharmaceutical industry or the production of biofuels. In this respect our research contributes to the field of synthetic biology.”

Looking towards the future

Haem and the specialised prosthetic group discovered here are examples of tetrapyrroles, a class of molecule that is being used in a variety of applications which can involve the synthesis of molecules that do not occur naturally. The new pathways described in this research involve novel enzymes, some of which have no obvious relations in other organisms.

Once the specificity and mechanisms of these enzymes are understood, they may be used in the production of designer tetrapyrroles, which could potentially be useful for the development of new materials, chemicals and medical treatments.

Having the ability to design new metabolic pathways, including those for the newly-discovered enzymes, and then building these into the laboratory work-horse organism E coli would make it possible to synthesise a variety of novel molecules.

To achieve this aim, the researchers will investigate the chemical logic underpinning the synthetic process, which is key for understanding biochemical pathways. Whilst this part of the story is only at the beginning, the possibilities for developments in synthetic biology are very exciting.

Further reading

Molecular hijacking of sirohaem for the synthesis of haem and d1 haem‘ (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) was published in Proceedings of the National Academy of Sciences, on 03 October.


Tracey Duncombe

tel: 01793 414695
fax: 01793 413382

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