An NIH shift is a chemical rearrangement where a hydrogen atom on an aromatic ring undergoes an intramolecular migration primarily during a

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

reaction. This process is also known as a 1,2-hydride shift. These shifts are often studied and observed by

isotopic labeling Isotopic labeling (or isotopic labelling) is a technique used to track the passage of an isotope (an atom with a detectable variation in neutron count) through a reaction, metabolic pathway, or cell. The reactant is 'labeled' by replacing specific ...

. An example of an NIH shift is shown below: In this example, a

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

atom has been isotopically labeled using

deuterium Deuterium (or hydrogen-2, symbol or deuterium, also known as heavy hydrogen) is one of two Stable isotope ratio, stable isotopes of hydrogen (the other being Hydrogen atom, protium, or hydrogen-1). The atomic nucleus, nucleus of a deuterium ato ...

(shown in red). As the hydroxylase adds a

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

(the −OH group), the labeled site shifts one position around the aromatic ring relative to the stationary

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

(−CH₃). Several hydroxylase enzymes are believed to incorporate an NIH shift in their mechanism, including

4-hydroxyphenylpyruvate dioxygenase 4-Hydroxyphenylpyruvate dioxygenase (HPPD), also known as α-ketoisocaproate dioxygenase (KIC dioxygenase), is an Fe(II)-containing non-heme oxygenase that catalyzes the second reaction in the catabolism of tyrosine - the conversion of 4-hydro ...

and the

tetrahydrobiopterin Tetrahydrobiopterin (BH4, THB), also known as sapropterin (INN), is a cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotoni ...

dependent

hydroxylase In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a m ...

s. The name ''NIH shift'' arises from the US

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the late ...

from where studies first reported observing this transformation.

References

* . * {{cite journal , author1=Bassan, A. , author2=Blomberg, M.R.A. , author3=Siegbahn, P.E.M. , title=Mechanism of Aromatic Hydroxylation by an Activated FeIV=O Core in Tetrahydrobiopterin-Dependent Hydroxylases , journal=Chem. Eur. J. , year=2003 , volume=9 , pages=4055–4067 , pmid=12953191 , doi=10.1002/chem.200304768 , issue=17. Enzymes Post-translational modification Reaction mechanisms