A team of UCL researchers recently discovered the function of Nit1, a metabolic repair enzyme. A lack of it could cause a metabolic disorder.
Our cells use oxygen to burn sugars and fat in order to generate ATP, the energy they need to function. ‘That’s the positive side of oxygen’, says UCL biochemistry Professor Émile Van Schaftingen. ‘But there’s also a downside: oxygen is very reactive and tends to damage certain molecules and proteins in our cells. This is called oxidant stress.’
Cysteine: an essential antioxidant
Some antioxidant substances combat the harmful effects of oxygen. One such substance is glutathione. This molecule, which is abundant in our cells, contains cysteine. ‘Cysteine is the active, antioxidant agent in glutathione’, explains Prof. Van Schaftingen. ‘And because our body is virtually incapable of producing cysteine on its own, it’s essential not to waste it.’
Enzymes are another substance at work in our cells. Sometimes they go after the wrong target and unexpectedly modify glutathione, rendering it inoperative and useless – rendering it, in other words, an abnormal metabolite. Abnormal metabolites can be harmful, especially if they accumulate.1 So the body has to get rid of them.
Nit1’s recycling mission
Our body has two ways of dealing with waste: it either throws it out and evacuates it (in urine or faeces, for example) or recycles it to serve some useful purpose. Damaged glutathione is usually recycled. ‘We discovered that Nit1, a metabolic repair enzyme, cuts off an initial piece of damaged glutathione in order to salvage its cysteine’, explains Prof. Van Schaftingen. ‘It’s a bit like a mechanic who dismantles a broken engine to salvage its parts.’
Nit1’s function was discovered through initial studies of the enzyme, purified by two members of Prof. Van Schaftingen’s team: Prof. Alessio Peracchi, on sabbatical at UCL from the University of Parma, and Dr Maria Veiga da Cunha. They then confirmed their hypothesis of Nit1’s role by analysing the urine of mice genetically modified to lack this enzyme. ‘Their urine contained damaged glutathione, which still contained its cysteine’, explains Prof. Van Schaftingen. ‘But the urine of normal mice contained none. This means that without the Nit1 enzyme, the recycling of damaged glutathione doesn’t occur.’
The discovery was the subject of an article in the American journal PNAS.2 It opens up interesting prospects.
Disease caused by damaged glutathione?
Prof. Van Schaftingen’s team has been studying the ‘misfires’ of metabolic enzymes and metabolic repair mechanisms for a decade. Their starting hypothesis (which was confirmed): if, owing to mutations in its encoding gene, a metabolic repair enzyme is lacking, a metabolic disorder can result.
In theory, treatment of such a disorder would involve mitigating the enzyme deficiency, for example by administering healthy enzymes or the gene that encodes them. In the case that interests us here, however, several facts have to be established first. ‘Firstly, we have to learn whether a Nit1 enzyme deficiency is possible and exists in humans’, says Prof. Van Schaftingen. ‘Secondly, even if it’s likely that a Nit1 deficiency exists, its symptoms must be determined. In the West, nutritional intake of cysteine is generally sufficient. In regions of the world where people lack protein, however, cysteine intake can be insufficient. A Nit1 enzyme deficiency would exacerbate a cysteine deficiency, which would surely produce symptoms.’3 The future will tell if anyone suffers from this affliction.
(1) See the article ‘Enzymes et maladies métaboliques’. (2) Peracchi, Veiga da Cunha et al., ‘Nit1 is a metabolite repair enzyme that hydrolyzes deaminated glutathione’, PNAS, March 2017. (3) The main source of cysteine intake is animal protein.
A glance at Émile Van Schaftingen's bio
1978 PhD, Medicine, UCL
1978-85 Teacher Education Thesis, de Duve Institute, UCL
1985-95 FNRS Research Associate1986-87 Postdoctorate, National Institutes of Health, Bethesda, Maryland, US
Since 1987 Director, research group, de Duve Institute
1992 Winner, Minkowski Prize
Since 1995 Biochemistry Professor, Faculty of Medicine, UCL
2003 Winner, Prix van Gysel
Since 2004 Director, de Duve Institute
Prof. Van Schaftingen’s research has been funded mainly by WELBIO, FNRS, UCL, the Belgian Fondation contre le Cancer and the sponsorship of the de Duve Institute.