Update of the LIPID MAPS comprehensive classification system for lipids

Abstract

In 2005, the International Lipid Classification and Nomenclature Committee under the sponsorship of the LIPID MAPS Consortium developed and established a “Comprehensive Classification System for Lipids” based on well-defined chemical and biochemical principles and using an ontology that is extensible, flexible, and scalable. This classification system, which is compatible with contemporary databasing and informatics needs, has now been accepted internationally and widely adopted. In response to considerable attention and requests from lipid researchers from around the globe and in a variety of fields, the comprehensive classification system has undergone significant revisions over the last few years to more fully represent lipid structures from a wider variety of sources and to provide additional levels of detail as necessary. The details of this classification system are reviewed and updated and are presented here, along with revisions to its suggested nomenclature and structure-drawing recommendations for lipids. In 2005, the International Lipid Classification and Nomenclature Committee under the sponsorship of the LIPID MAPS Consortium developed and established a “Comprehensive Classification System for Lipids” based on well-defined chemical and biochemical principles and using an ontology that is extensible, flexible, and scalable. This classification system, which is compatible with contemporary databasing and informatics needs, has now been accepted internationally and widely adopted. In response to considerable attention and requests from lipid researchers from around the globe and in a variety of fields, the comprehensive classification system has undergone significant revisions over the last few years to more fully represent lipid structures from a wider variety of sources and to provide additional levels of detail as necessary. The details of this classification system are reviewed and updated and are presented here, along with revisions to its suggested nomenclature and structure-drawing recommendations for lipids. In an effort to support the growing field of lipidomics and establish the importance of lipids as a major class of biomolecules, the International Lipid Classification and Nomenclature Committee (ILCNC) developed a “Comprehensive Classification System for Lipids” that was published in 2005 (1Fahy E. Subramaniam S. Brown H.A. Glass C.K. Merrill Jr., A.H. Murphy R.C. Raetz C.R. Russell D.W. Seyama Y. Shaw W. al et A comprehensive classification system for lipids.J. Lipid Res. 2005; 46: 839-862Abstract Full Text Full Text PDF PubMed Scopus (1141) Google Scholar). For the purpose of classification, we define lipids as hydrophobic or amphipathic small molecules that may originate entirely or in part by carbanion-based condensations of thioesters (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides) and/or by carbocation-based condensations of isoprene units (prenol lipids and sterol lipids). The comprehensive classification system organizes lipids into these eight well-defined categories (Table 1) that cover eukaryotic and prokaryotic sources. It has been adopted internationally and widely accepted by the lipidomics community. The system is also available online on the LIPID MAPS (2Schmelzer K. Fahy E. Subramaniam S. Dennis E.A. The lipid maps initiative in lipidomics.Methods Enzymol. 2007; 432: 171-183Crossref PubMed Scopus (115) Google Scholar) website (http://www.lipidmaps.org). The comprehensive classification system has been under the guidance of the ILCNC, 3The ILCNC currently consists of Dr. Edward A. Dennis, Chair, (US), Dr. Robert C. Murphy (US), Dr. Masahiro Nishijima (Japan), Dr. Christian R. H. Raetz (US), Dr. Takao Shimizu (Japan), Dr. Friedrich Spener (Austria), Dr. Gerrit van Meer (The Netherlands), and Dr. Michael Wakelam (UK). Dr. Shankar Subramaniam serves as Informatics Advisor, and Dr. Eoin Fahy serves as Director. Meetings were held May 7, 2006 and May 4, 2008 in La Jolla, CA. which meets periodically to propose changes and updates to classification, nomenclature, and structural representation.TABLE 1Lipid categories of the comprehensive classification system and the number of structures in the LIPID MAPS databaseCategoryAbbreviationStructures in DatabaseFatty acylsFA2678GlycerolipidsGL3009GlycerophospholipidsGP1970SphingolipidsSP620Sterol LipidsST1744Prenol LipidsPR610SaccharolipidsSL11PolyketidesPK132 Open table in a new tab The initial version of the comprehensive classification system was more heavily focused on mammalian lipids, reflecting a bias toward the experimental interests of the LIPID MAPS Consortium (2Schmelzer K. Fahy E. Subramaniam S. Dennis E.A. The lipid maps initiative in lipidomics.Methods Enzymol. 2007; 432: 171-183Crossref PubMed Scopus (115) Google Scholar). However, due to considerable attention and requests from lipid researchers in a variety of fields, the classification system has now been extended to more fully represent lipid structures from nonmammalian sources, such as plants, bacteria, and fungi. For example, two new main classes (Glycosyldiradylglycerols and Glycosylmonoradylglycerols) have been added to the Glycerolipids category to accommodate key plant structural lipids, such as the sulfoquinovosyldiacylglycerols (3Norman H.A. Mischke C.F. Allen B. Vincent J.S. Semi-preparative isolation of plant sulfoquinovosyldiacylglycerols by solid phase extraction and HPLC procedures.J. Lipid Res. 1996; 37: 1372-1376Abstract Full Text PDF PubMed Google Scholar) found in chloroplasts. Also, the list of subclasses under the Sterols main class has been expanded to include a set of 15 different core structures (Ergosterols, Gorgosterols, Furostanols, etc.), which provide a structure-based classification of these molecules that span multiple phyla. Another key development has been the adoption of existing hierarchies (4Buckingham J. Dictionary of Natural Products on CD-ROM, Version 6.1. Chapman & Hall, London1998Crossref Google Scholar) for the Polyketide category and Prenol Lipids/Isoprenoids subclasses where the majority of these molecules are derived from natural product sources and have been studied intensively from a pharmaceutical and ecological standpoint. This in turn has necessitated the expansion of the number of existing classification levels (category, main class, and subclass) to accommodate an additional level of stratification in the case of the C10 to C30 isoprenoid subclasses that now contain entries at a fourth level of detail. The “LM_ID” identifier, whose format provides a systematic means of assigning a unique identification to each lipid molecule, has accordingly been expanded in length in these particular cases, with an additional two characters being used to describe the fourth level. A detailed overview of the changes and updates to the comprehensive classification system is presented below. As a consequence of adding an extra level of classification detail, the length of the LM_ID identifier was lengthened from 12 characters to 14 in cases where a lipid defined with four levels of classification is being described (Table 2). In this case, characters 9 and 10 specify the level-4 class. It should be emphasized that all lipids that do not require a fourth level of detail (i.e., the vast majority of them) still use a 12-digit LM_ID identifier.TABLE 2Format of LIPID MAPS identifier (LM_ID) in the comprehensive classification systemCharactersDescriptionExampleComments1–2Fixed “LM” designationLMAlways LM3–4Two-letter category codePROne of eight categories5–6Two-digit class code01—7–8Two-digit subclass code03“00” when no subclass9–10Two-digit fourth level code06Only used for lipids with four levelsLast four digitsUnique four-character identifier within subclass or within fourth level0002First two of the last four digits are letters in the case of the Glycosphingolipid subclasses Open table in a new tab In keeping with the theme of having a classification system dictated by molecular structure and function, the sterol lipid subclasses Phytosterols, Marine sterols, and Fungal sterols were retired because these refer to the lipid source (marine) or biological kingdom (plants and fungi). It is possible to identify a particular sterol in more than one of these three sources. These subclasses have been replaced by a new set of subclasses based on the carbon skeleton of the sterol core structure (Ergosterols, Gorgosterols, Furostanols, etc.). The details are outlined under the Sterol Lipids section below, and the complete description of this category can be found on the LIPID MAPS website 4Supplementary tables that provide the complete list of the classes, subclasses, and fourth class level (where applicable) of each of the eight categories of lipids are available on the LIPID MAPS website at http://www.lipidmaps.org. (http://www.lipidmaps.org). The natural products chemistry and medicinal chemistry literature describes tens of thousands of molecules that fall under the scope of lipids, based on their biosynthetic origin. In particular, isoprenoids and polyketides from diverse sources, such as plant, fungi, algae, bacteria, and marine invertebrates, are well documented and have been reviewed and classified in detail. The Dictionary of Natural Products (4Buckingham J. Dictionary of Natural Products on CD-ROM, Version 6.1. Chapman & Hall, London1998Crossref Google Scholar), a database available from Chapman and Hall/CRC (http://dnp.chemnetbase.com), has a classification hierarchy that covers polyketides and isoprenoids in depth. The LIPID MAPS comprehensive classification system has now incorporated some of these hierarchies relevant to natural products, with a view to covering both mammalian and nonmammalian lipids comprehensively. 3The ILCNC currently consists of Dr. Edward A. Dennis, Chair, (US), Dr. Robert C. Murphy (US), Dr. Masahiro Nishijima (Japan), Dr. Christian R. H. Raetz (US), Dr. Takao Shimizu (Japan), Dr. Friedrich Spener (Austria), Dr. Gerrit van Meer (The Netherlands), and Dr. Michael Wakelam (UK). Dr. Shankar Subramaniam serves as Informatics Advisor, and Dr. Eoin Fahy serves as Director. Meetings were held May 7, 2006 and May 4, 2008 in La Jolla, CA. It was recognized that additional levels of stratification were required to classify certain types of lipids and that the current three-level system of category/main class/subclass needed to be expanded. For example, in the Prenol Lipids category, 3The ILCNC currently consists of Dr. Edward A. Dennis, Chair, (US), Dr. Robert C. Murphy (US), Dr. Masahiro Nishijima (Japan), Dr. Christian R. H. Raetz (US), Dr. Takao Shimizu (Japan), Dr. Friedrich Spener (Austria), Dr. Gerrit van Meer (The Netherlands), and Dr. Michael Wakelam (UK). Dr. Shankar Subramaniam serves as Informatics Advisor, and Dr. Eoin Fahy serves as Director. Meetings were held May 7, 2006 and May 4, 2008 in La Jolla, CA. the Sesquiterpene C15 subclass contains ∼90 known variants based on their carbon skeletons (Bisabolanes, Germacranes, etc.). A fourth level of detail has been added to the LIPID MAPS comprehensive classification system to handle cases such as these. In response to worldwide interest in the comprehensive classification system for lipids, the scope has been expanded to cover lipids from nonmammalian sources, such as plants, bacteria, fungi, algae, and marine organisms. To accomplish this, several new lipid classes have been added, such as fatty acyl glycosides, glycosyldiradylglycerols, and various sterol skeletons. The Polyketide category has also been revised comprehensively. 3The ILCNC currently consists of Dr. Edward A. Dennis, Chair, (US), Dr. Robert C. Murphy (US), Dr. Masahiro Nishijima (Japan), Dr. Christian R. H. Raetz (US), Dr. Takao Shimizu (Japan), Dr. Friedrich Spener (Austria), Dr. Gerrit van Meer (The Netherlands), and Dr. Michael Wakelam (UK). Dr. Shankar Subramaniam serves as Informatics Advisor, and Dr. Eoin Fahy serves as Director. Meetings were held May 7, 2006 and May 4, 2008 in La Jolla, CA. The nomenclature of lipids falls into two main categories: systematic names and common or trivial names. The latter includes abbreviations that are a convenient way to define acyl/alkyl chains in acylglycerols, sphingolipids, and glycerophospholipids and synonyms such as “phosphatidyl” for “glycerophospho.” The generally accepted guidelines for lipid systematic names have been defined by the International Union of Pure and Applied Chemists and the International Union of Biochemistry and Molecular Biology (IUPAC-IUBMB) Commission on Biochemical Nomenclature (http://www.chem.qmul.ac.uk/iupac/) (5IUPAC-IUB Commission on Biochemical Nomenclature (CBN). The nomenclature of lipids (Recommendations 1976). 1977. Eur. J. Biochem. 79: 11–21; 1977. Hoppe-Seylers Z. Physiol. Chem. 358: 617–631; 1977. Lipids 12: 455–468; 1977. Mol. Cell. Biochem. 17: 157–171; 1978. Chem. Phys. Lipids 21: 159–173; 1978. J. Lipid Res. 19: 114–128; 1978. Biochem. J. 171: 21–35. (http://www.chem.qmul.ac.uk/iupac/lipid/).Google Scholar, 6I. U. P. A. C-I. U. B. Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of glycolipids. (Recommendations 1997) 2000. Adv. Carbohydr. Chem. Biochem. 55: 311–326; 1988. Carbohydr. Res. 312: 167–175; 1998. Eur. J. Biochem. 257: 293–298; 1999. Glycoconjugate J. 16:1–6; 1999. J. Mol. Biol. 286: 963–970; 1997. Pure Appl. Chem. 69: 2475–2487. (http://www.chem.qmul.ac.uk/iupac/misc/glylp.html)Google Scholar, 7I. U. P. A. C-I. U. B. Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of prenols. (Recommendations 1987) 1987. Eur. J. Biochem. 167: 181–184. (http://www.chem.qmul.ac.uk/iupac/misc/prenol.html)Google Scholar, 8I. U. P. A. C-I. U. B. Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of steroids (Recommendations 1989) 1989. Eur. J. Biochem. 186: 429–458. (http://www.chem.qmul.ac.uk/iupac/steroid/).Google Scholar). In response to several requests from knowledgeable lipid experts, abbreviations for Glycerophospholipid classes (see http://www.lipidmaps.org for GP category 3The ILCNC currently consists of Dr. Edward A. Dennis, Chair, (US), Dr. Robert C. Murphy (US), Dr. Masahiro Nishijima (Japan), Dr. Christian R. H. Raetz (US), Dr. Takao Shimizu (Japan), Dr. Friedrich Spener (Austria), Dr. Gerrit van Meer (The Netherlands), and Dr. Michael Wakelam (UK). Dr. Shankar Subramaniam serves as Informatics Advisor, and Dr. Eoin Fahy serves as Director. Meetings were held May 7, 2006 and May 4, 2008 in La Jolla, CA.) have been changed now in the comprehensive classification system to the more universally used two-letter “PC/PE/PS/PA/PI” format. Consequently, glycerophospholipids in the LIPID MAPS structure database and LIPID MAPS standards database as well as all the Glycerophospholipids drawing tools and mass spectrometry prediction tools have been updated to conform to this new abbreviation format (Table 3).TABLE 3Changes in abbreviations for Glycerophospholipids in the comprehensive classification systemClassSynonymOldNewGlycerophosphocholinesPhosphatidylcholinesGPChoPCaFor abbreviations of monoradyglycerophospholipids (lysophospholipids), LPX may be used, for example, LPC, LPE, LPA, etc.GlycerophosphoethanolaminesPhosphatidylethanolaminesGPEtnPEGlycerophosphoserinesPhosphatidylserinesGPSerPSGlycerophosphoglycerolsPhosphatidylglycerolsGPGroPGGlycerophosphoglycerophosphatesPhosphatidylglycerol phosphatesGPGroPPGPGlycerophosphoinositolsPhosphatidylinositolsGPInsPIGlycerophosphoinositol monophosphatesPhosphatidylinositol phosphatesGPInsPPIPGlycerophosphoinositol bis-phosphatesPhosphatidylinositol bis-phosphatesGPInsP2PIP2Glycerophosphoinositol For abbreviations of monoradyglycerophospholipids (lysophospholipids), LPX may be used, for example, LPC, LPE, LPA, Open table in a new tab The LIPID MAPS Consortium has considerable effort to establish guidelines for drawing lipid structures in a and and lipids are to which to the use of unique that more than the lipid community. the structure-drawing is the in molecular of lipids. However, classes of lipids well as for structure-drawing due to their A of structure-drawing tools has been developed and that of systematic and abbreviations E. Subramaniam S. LIPID MAPS online tools for lipid Res. 2007; PubMed Scopus Google Scholar). The structures may be and in a variety of of the structure-drawing tools for fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterols are available in the section of the LIPID MAPS website (http://www.lipidmaps.org). of the structures are in the importance of these molecules in and is to have a database of lipids with a defined ontology that is extensible, flexible, and scalable. The ontology of lipids classification, nomenclature, structure and structural of all in the have developed a available comprehensive database of lipid structures of lipid molecules from existing and from the LIPID MAPS This database Fahy E. Brown A. Dennis E.A. Glass C.K. Merrill Jr., A.H. Murphy R.C. Raetz C.R. Russell D.W. al et LIPID MAPS structure Res. 2007; PubMed Scopus Google Scholar, E. R. A. J. Y. Subramaniam S. for lipidomics.Methods Enzymol. 2007; 432: PubMed Scopus Google Scholar), in to as the to and of lipid also contains systematic classification, nomenclature, and structure of lipids along with mass where than lipid molecules are now available on the LIPID MAPS and these have been adopted by the for as well as the of and database structures have been classified and to LIPID MAPS A number of different molecular such as and the and are and nomenclature of these molecules are also The database is and the include and structure-based the category, the subclasses and have been changed to and to accommodate The names of the fatty subclasses and have been to and A new acyl main class has been added to cover the number of found in bacteria, and marine of natural of fatty and PubMed Scopus Google Scholar, and of the natural PubMed Scopus Google Scholar). subclasses include acyl of and and The Glycerolipids category was to include two new main classes (Glycosyldiradylglycerols and Glycosylmonoradylglycerols) that contain key plant structural lipids, such as the found in chloroplasts. The existing subclasses were to the that is to the of on the for and of structures in the LIPID MAPS structure database have been For with two different two different structural are for with three different different of drawing all possible structural an is used as a A along with the number of possible is to the abbreviation and and a unique LM_ID is of this format is the The structure to the LM_ID on the LIPID MAPS website to the in the and the is to all in the are also cases within the and classes where are due to by certain of both the or to and where the of the at is by the acyl from the of to the at or can an In such cases when a is can be with a for example, or the is with a for example, It should be that the two-letter abbreviation or all possible types of lipid for example, having and The is by the for example, and the by the for example, The to the classes within the Glycerophospholipids In cases where is and is abbreviations such as and may be used, where the within refer to the number of and of all the For the Glycerophospholipids category, the subclass has been replaced by the more due to the that in are the in H.A. J.S. S. in and PubMed Scopus Google Scholar). updates have been for the Glycerophospholipid The lipids class has been replaced by the class to of with than As we have changed to two-letter abbreviations to describe glycerophospholipids in are abbreviations for all molecular of their These names to and are used widely in lipid as to systematic names. This format one or two chains where the structures of the chains are within is at the carbon of and the is at the In cases of molecules with at of the and of the at the the of is to the abbreviation and the abbreviation format is for molecules with at the carbon of the the of is to the and the structure is with In cases where is and is such as may be used to of and for all and are by an or identifier, as in and In the latter case, the an at of and a at the or may be with a in the for example, The “phosphatidyl” is used to refer to classes all types of chains and not acyl as was by guidelines (5IUPAC-IUB Commission on Biochemical Nomenclature (CBN). The nomenclature of lipids (Recommendations 1976). 1977. Eur. J. Biochem. 79: 11–21; 1977. Hoppe-Seylers Z. Physiol. Chem. 358: 617–631; 1977. Lipids 12: 455–468; 1977. Mol. Cell. Biochem. 17: 157–171; 1978. Chem. Phys. Lipids 21: 159–173; 1978. J. Lipid Res. 19: 114–128; 1978. Biochem. J. 171: 21–35. (http://www.chem.qmul.ac.uk/iupac/lipid/).Google Scholar). The classification is from that in the in this (2Schmelzer K. Fahy E. Subramaniam S. Dennis E.A. The lipid maps initiative in lipidomics.Methods Enzymol. 2007; 432: 171-183Crossref PubMed Scopus (115) Google Scholar). of is that for of the Glycosphingolipid subclasses, the structure of the is known the structure of the is In these cases, the last two digits of the LIPID MAPS LM_ID identifier are as to an and the and fourth last digits are a different two-letter identifier for unique within that For example, in the subclass the structure is an LM_ID of where the digits specify the unique and the digits a the has a and is a LM_ID of The Sterol lipids subclasses Phytosterols, Marine sterols, and Fungal sterols have been and replaced with a set of subclasses (Ergosterols, sterols, Gorgosterols, Furostanols, and that in the of their sterol core structures and cover multiple A. Sterols in marine Scopus Google Scholar, Phytosterols, and their in structural and Lipid Res. PubMed Scopus Google Scholar). The class has been with the and the class now includes and The class has been to the Prenol Lipids category the of the core structure is at with the of the of the Sterol Lipids The subclass of the Prenol lipids category has been added to the class. are a of that are to A. have in of and As the C10 to C30 isoprenoid subclasses now contain entries at a fourth level of detail. The LM_ID contain an extra two digits that specify the fourth level class, for example, the is an LM_ID of The class has been to the Prenol Lipids category the Sterol Lipids For the the main class acyl has been added to cover a variety of from plants, bacteria, and fungi. is the from the plant and from the of Scopus Google Scholar). It should be that this category covers structures in which fatty acyl/alkyl are to a lipids to a are found in their The category was revised and on the classification hierarchy used by the Dictionary of Natural Products (4Buckingham J. Dictionary of Natural Products on CD-ROM, Version 6.1. Chapman & Hall, London1998Crossref Google Scholar). are from bacteria, fungi, plants, and and have been heavily studied by natural products and for The new classification format provides a of the structural within this The toward classification of lipids is the of an ontology that is extensible, flexible, and scalable. be to and represent these molecules in a that is to databasing and The ILCNC the comprehensive classification system in 2005 and has been in and on a to considerable attention and requests from lipid researchers in a variety of fields, the classification system has been extended to more fully represent lipid structures from nonmammalian sources, such as plants, bacteria, and fungi. This system has been internationally accepted and is now widely used in and for The LIPID MAPS classification system has also been adopted by where hierarchies lipids, and have been and by the in format of the In an effort to LIPID MAPS lipid structures are now available on website where have been The classification system is available online where has been with an database of lipids. This in to as the and of lipid also contains systematic classification, nomenclature, and structure of lipids along with mass where structures have been classified and to LIPID MAPS The format of the LM_ID identifier (Table provides a systematic means of the classification hierarchy and assigning a unique identification to each lipid It also for the of new classification in the The database is and the include and structure-based This database is described in detail Fahy E. Brown A. Dennis E.A. Glass C.K. Merrill Jr., A.H. Murphy R.C. Raetz C.R. Russell D.W. al et LIPID MAPS structure Res. 2007; PubMed Scopus Google Scholar, E. R. A. J. Y. Subramaniam S. for lipidomics.Methods Enzymol. 2007; 432: PubMed Scopus Google Scholar). A of lipid structure-drawing tools in the section of the LIPID MAPS has been developed to structure with LIPID MAPS These tools are also of systematic names and detailed and databasing of lipid and has been to and database and to classify and LIPID MAPS These tools be expanded and as the scope of the classification system and over the The the of lipid researchers around the have and to attention in the Classification System for which to be to new and in the lipid The are also to the LIPID MAPS Consortium for their and to Dr. at the of for to this