inchi-isotopologue-extension

specification extension to InChi to better support isotopologue reporting

Purpose:

Develop enhanced specifications within the regular InChI standard for representing isotopologues and isotopomers. More specifically, augment the isotopic layer specifications of the regular InChI standard so that specific isotopologues, isotopomers, partial isotopomers, and isotopologue fragments can be represented by a single InChI string and used to identify isotope-informative analytical features.

Current Team Members:

• Hunter Moseley - University of Kentucky, Lexington, KY, USA.
• Philippe Rocca-Serra - University of Oxford e-Research Centre, Department of Engineering Science, Oxford, UK.
• Reza Salek - International Agency for Research on Cancer, WHO, 150 cours Albert Thomas 69372 Lyon CEDEX 08, France.
• Masanori Arita - National Institute of Genetics, Yata 1111, Mishima, 411-8540 Shizuoka, Japan.
• Emma Schymanski - Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg.

Problems Being Solved:

While the InChI standard has an isotopic layer for representing exact isotopomers, there is not a specification for representing a range (set) of isotopomers. The fundamental issue is that an ambiguous location of specific isotopes of certain atoms cannot be represented in the current standard. This is needed to represent a set of isotopomers that correspond to a specific isotopologue. Currently, an InChI string can represent a specific isotopomer, but not a set of mass-equivalent isotopomers.

• For example, here is the InChI string for alpha-D-glucopyranose:

InChI=1S/C6H12O6/c7-1-2-3(8)4(9)5(10)6(11)12-2/h2-11H,1H2/t2-,3-,4+,5-,6+/m1/s1

SMILES=C([C@@H]1[C@H]([C@@H]([C@H]([C@@H](O)O1)O)O)O)O view

• The following InChI string represents the explicit 13C isotopomer with the 4th carbon labeled:

InChI=1S/C6H12O6/c7-1-2-3(8)4(9)5(10)6(11)12-2/h2-11H,1H2/t2-,3-,4+,5-,6+/m1/s1/i1+0,2+0,3+0,4+1,5+0,6+0

SMILES=[12CH2]([12C@@H]1[12C@H]([13C@@H]([12C@H]([12C@@H](O)O1)O)O)O)O viewO&abbr=off&hdisp=bridgehead&showtitle=false&zoom=1.55&annotate=none)

However, there is no way to create a single valid InChI string that represents the isotopologue of alpha-D-glucopyranose containing one ¹³C atom at an undefined atomic location, which is the signal that would be observed in mass spectrometry experiments. The use of multiple InChI strings to represent this is impractical for many isotopologues.

Proposed Isotopologue Extension for InChI

The full proposal can be found here.

• definitions

• existing iupac specifications (2018, prior to proposal)

• proposed iupac specifications extension

• iupac feedback - Questions and Answers

Community Feedback:

We are actively seeking feedback on this proposal from the broader scientific community.

The community consultation about the proposed specifications is now closed and the proposal has been submitted to the IUPAC in , which has since accepted the specifications, allowing initial implementation efforts.

However, we welcome comments, suggestions for improvements and reporting of issues with the specifications themselves, the documentation and text found in this repository.

There are three ways to provide this feedback.

1. Post an issue on this repository.

2. Submit a comment via this Google Form.

3. Create a PDF from the full proposal, mark it up, and email it to: hunter.moseley@gmail.com

Please use the following subject line: “InChI Isotopologue Proposal Feedback”.

Tasks:

• Develop a more complete InChI isotopic layer specification and examples for isotopologues, isotopomers, partial isotopomers, and isotopologue fragments for naming isotopically-resolved molecular features detectable by analytical instrumentation. COMPLETED (TODO: add date: YYYY.MM.DD)

• Develop InChI isotopic layer specification and examples for non-isotopically-resolved isotopologues detected by less resolved/accurate mass analytical instrumentation. COMPLETED (TODO: add date: YYYY.MM.DD)

• Review and refine developed specifications. COMPLETED (TODO: add date: YYYY.MM.DD)

• Present proposed specifications to the IUPAC InChI subcommittee and the InChI Trust. COMPLETED (TODO: add date: YYYY.MM.DD)

Softwares implementing the specification:

1. Implementation of the isotopomer portion of the specification:

   The isoenum and isoenum-webgui python packages are the only currently available implementation of the isotopomer portion of the specification. These tools are developed in the Moseley Lab:

• isoenum

• isoenum-webgui

1. Implementation of the isotopologue portion of the specification

The next part is to develop software that uses the isotopologue portion of the specification. However, this requires an SDFile representation of isotopologues. A draft SDFile representation for isotopologues that utilizes masking MOL file entries is currently under review by the InChI software implementers.

Use cases: reporting of stable isotope resolved metabolomics experiments

1. Experiments submitted to the US repository, Metabolomics Workbench.

NMR based study ST001139

Exemplar tabular representation in the MWTab format, `Metabolites` section:

metabolite_name	base_inchi	isotopic_inchi	peak_description	peak_pattern	proton_count	representative_inchi	transient_peak
Ala-3_1	InChI=1S/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1	InChI=1/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1/i1H3,2H/f/h4H	[1H7,1H8,1H9:C1]HResonance + [1H7,1H8,1H9:1H10]J3HH	doublets	3	InChI=1/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1/f/h4H	1
Ala-3_2	InChI=1S/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1	InChI=1/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1/i1H3,2H/f/h4H	[1H7,1H8,1H9:C1]HResonance + [1H7,1H8,1H9:1H10]J3HH	doublets	3	InChI=1/C3H7NO2/c1-2(4)3(5)6/h2H,4H2,1H3,(H,5,6)/t2-/m0/s1/f/h4H	2

1. Experiments submitted to the European repository, EMBL-EBI Metabolights.

MS based study MTBLS412