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Naming the Cycle: On the Etymology of the Citric Acid Cycle Intermediates Peter Polcǐ c*
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Department of Biochemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská dolina CH-1, Ilkovičova 6, Bratislava 84215, Slovak Republic ABSTRACT: In biochemistry, the trivial names of chemical compounds constitute a significant part of scientific language. Understanding the etymology of the names may be important for the association of these names with actual compounds and thus be a valuable teaching tool. The citric acid cycle (Krebs cycle) is a central metabolic pathway in most living cells. Intermediates of the cycle play important roles in cellular metabolism, and their names reappear in the names of many derived compounds in other metabolic pathways. In this article, information on the origins of names of the citric acid cycle intermediates is provided. KEYWORDS: General Public, Biochemistry, Communication/Writing, Metabolism, History/Philosophy, Bioenergetics
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INTRODUCTION As students of biochemistry proceed through the curriculum from general chemistry to the introductory course of biochemistry, an increasing number of students perceive the new compounds they learn as abstract formulas and unfamiliar trivial names, mostly with little association to the actual chemical compounds. Learning the biochemical pathways thus often turns into a challenge of memorizing the sequences of the names. Mnemonics are often employed to help memorize compound classification or metabolic pathways. These, however, only make memorization easier without providing any useful insight or even motivation. Alternative approaches may be far more desirable. One such approach would involve providing the students with information on the etymology of the names of the compounds involved. Using this approach in the classroom (e.g., biochemistry seminars) appears to be a valuable teaching tool that helps the students to develop an awareness of the individual compounds and to fix the memorized knowledge of compound names. The feedback provided by students also indicates that it may even spark their interest and motivate them to study further beyond the textbook knowledge (e.g., to provoke an interest in the history of science). The importance of understanding etymology is wellrecognized for general scientific terms, most of which are derived from Ancient Greek or Latin.1−3 Origins of the names of chemical elements4 as well as the etymology of trivial names of several organic compounds5 have also been reviewed. Origins of many trivial names used in biochemistry are, however, slowly becoming forgotten and are often hard to trace in the original literature. Here, the etymology of the names of compounds associated with the citric acid cycle, a pathway that is unique for its key role in cellular metabolism, is reviewed. Unlike many other metabolic pathways, in which often systematic chemical names of intermediates are used, almost all intermediates of the citric acid cycle are known by their trivial names that do not etymologically relate to the chemistry of the pathway. Including the etymology of © XXXX American Chemical Society and Division of Chemical Education, Inc.
intermediates’ names into teaching the metabolic pathways, especially in the case of the citric acid cycle, may thus represent a novel approach to teaching metabolism and may effectively complement the textbook knowledge by filling the gap between the chemistry and the terminology.
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ETYMOLOGY OF CITRIC ACID CYCLE INTERMEDIATES The citric acid cycle (CAC), which is also known as the Krebs cycle after Hans Krebs who discovered it together with William Johnson, is a central metabolic pathway in most living cells.6 Products of degradation of saccharides, fatty acids, or amino acids are oxidized in the CAC to carbon dioxide, and electrons are fed to the respiratory chain and ultimately transferred to oxygen. Saccharides enter the CAC after they are converted to pyruvate by the glycolytic pathway. Pyruvate is first decarboxylated by pyruvate dehydrogenase complex to produce acetyl-coenzyme A, which reacts with oxaloacetate to produce citrate. Fatty acids enter the CAC as acetylcoenzyme A that is a product of their β-oxidation. Like the names of most of the CAC intermediates, the name pyruvate reflects the natural source from which it was prepared at the time of its discovery. Pyruvic acid (2-oxopropanoic acid) has been known since 1835 when Jöns Jacob Berzelius prepared it by dry distillation of tartaric and racemic acid (the optically inactive mixture of the tartaric acid and its enantiomer).7 He named the newly prepared acid “acidum pyruvicum” from Greek pyr (πυρ) = fire, to reflect the method by which it was prepared, and Latin uva = grape, to reflect its origin in acids, which relate to grapes. The names of these two acids had been derived from cream of tartar, a winemaking byproduct (potassium hydrogen tartrate), and the Latin racemus = a bunch of grapes, respectively. Received: January 27, 2018 Revised: July 16, 2018
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DOI: 10.1021/acs.jchemed.8b00059 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Communication
Table 1. Overview of the Origin of Trivial Names Associated with the CAC Compound
Name Origina
Note
pyruvic acid
pyr (Gk.) = fire, uva (Lat.) = grape
racemic acid tartaric acid citric acid aconitic acid α-ketoglutaric acid glutamic acid succinic acid fumaric acid malic acid oxaloacetic acid oxalic acid acetic acid guanosine triphosphate (GTP) guanine
racemus (Lat.) = a bunch of grapes cream of tartar citron (Swe.) = lemon plant Aconitum (monk’s-hood or wolfsbane) keto-, glutamic acid gluten, amino acid succinum (Lat.) = amber plant Fumaria off icinalis (common fumitory) malum (Lat.) = apple oxalic acid, acetic acid plant Oxalis acetum (Lat.) = vinegar
nicotinamide adenine dinucleotide (NAD+) nicotine adenine flavin adenine dinucleotide (FAD) flavin thiamine pyrophosphate (TPP) thiamine pyrophosphate lipoic acid
first prepared by heating acids derived from grape (tartaric acid and racemic acid) found in grapes cream of tartar is a salt of racemic acid first isolated from lemon juice first isolated from Aconitum plant keto derivative of glutamic acid, prefix keto- is derived from acetone first prepared from gluten first prepared from amber first isolated from Fumaria plant first isolated from apple juice first isolated from Oxalis plant found in vinegar
guano (Sp., from Quechua) = seabirds’ excrements
first isolated from guano
Nicotiana tabacum = tobacco plant adenas (Gk.) = gland
first isolated from tobacco first isolated from bovine pancreas
f lavus (Lat.) = yellow
functional group of the yellow-colored vitamin (riboflavin)
theio (Gk.) = sulfur, vitamin pyr (Gk.) = fire, phosphate lipos (Gk.) = fat
sulfur-containing vitamin first prepared from the phosphoric acid by heating lipophilic compound required for biosynthesis of fatty acids
a
Gk., Greek; Lat., Latin; Swe., Swedish; Sp., Spanish.
The name of oxaloacetate (oxobutanedioic acid) is derived from names of acetic acid (from Latin acetum = vinegar) and oxalic acid (from plant genus Oxalis, whose leaves contain oxalic acid, which gives them the sour taste; the name of the plant therefore comes from ancient Greek oxýs (òξῠ́ς) = sharp, acid). Citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid) was isolated for the first time by crystallization from lemon juice by Carl Wilhelm Scheele in 1784. In an article written in German, he refers to the acid as citronensaure8 from the Swedish citron = lemon. This name was later adapted in German to Zitronensäure and eventually to its current English name (likely also influenced by Latin citrus = genus to which the lemon (Citrus limon) belongs). Aconitic acid (prop-1-ene-1,2,3-tricarboxylic acid), an intermediate of the isomerization of citrate to isocitrate in the CAC, was first isolated in 1820 by Jacques Peschier from the herbs Aconitum napellus and Aconitum paniculatum (in English known as monk’s-hood or wolfsbane).9 The name of the acid was thus derived from the genus name of these plants. Isocitrate (1-hydroxypropane-1,2,3-tricarboxylic acid), an isomer of citrate, is then oxidatively decarboxylated to αketoglutarate (2-oxopentanedioic acid). The name α-ketoglutarate is derived from the name of a related amino acid, glutamic acid (2-aminopentanedioic acid), which was first identified in hydrolyzed protein obtained from wheat gluten, hence its name (originally Glutaminsäure in German).10,11 The prefix “keto-”, indicating the presence of a carbonyl group, originates from the word keton that is derived from acetone.12 Acetone was named after acetic acid when it was recognized as its derivative.13
In subsequent reactions, succinyl-CoA is formed by the oxidative decarboxylation of α-ketoglutarate, and succinate is produced by the cleavage of the thioester bond in succinylCoA. Interestingly, succinic acid (butanedioic acid) was first prepared more than two hundred years before citric acid and was one of the first organic acids available. It was prepared by dry distillation of Baltic amber around 1546 by Georgius Agricola. As he believed it to be a salt, he called it “f lores succini” from the Latin succinum = amber. After it was shown to be an acid by Lemery, it became “acide du succini” and later succinic acid (originally acide succinique in French).14 Succinate is oxidized to fumarate (trans-butenedioic acid), which is hydrated to form malate (2-hydroxybutanedioic acid). Fumaric acid was isolated and characterized by F. L. Winkler in 1832,15 who isolated it from Extract Fumarie, an extract from a common fumitory (Fumaria off icinalis). The Latin name of this plant, from which the name of the acid is derived, reportedly comes from the Latin “f umes de terre” (smoke of the earth) and refers to the appearance of the plants that resembles smoke rising from the ground. Malic acid was first described by Scheele in 1785 when it was isolated from unripe apple juice. In a paper written in Swedish, it was named accordingly as Åple-syra (acid of apple). The name malic acid, from the Latin malum = apple, was later adapted (originally acide malique in French).14 The oxidation of malate then brings us back to oxaloacetate and completes the cycle. To conclude the list of the names and their origins, one also has to look at the names of cofactors that participate in the CAC reactions. Those with names of an interesting origin, other than systematic chemical names, include guanosine triphosphate (GTP), nicotinamide adenine dinucleotide, flavin B
DOI: 10.1021/acs.jchemed.8b00059 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
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ACKNOWLEDGMENTS The author thanks Katarina Polčicová for critically reading the manuscript, William Tibbits for improving the English, and the reviewers of the manuscript for offering helpful suggestions.
adenine dinucleotide, thiamine pyrophosphate, and lipoic acid. Names of the three nucleotides contain names of their components, which are guanine, a nucleobase first isolated from guano, the excrement of seabirds;16 adenine, another base that was first isolated from bovine pancreas (adenas (αδενας) = gland);17 flavin, a functional group that was first described as a component of the yellow-colored vitamin (riboflavin) present in milk (from Latin f lavus = yellow);18 and nicotinamide, an amide of nicotinic acid, a vitamin, whose name is derived from the name of another compound, nicotine, from which it was prepared for the first time.19 The name nicotine comes from the Latin name of the tobacco plant (Nicotiana tabacum),20 named after Jean Nicot, the 16th century French diplomat who served as an ambassador in Portugal from where he introduced the tobacco plant to France. Thiamine pyrophosphate (TPP) and lipoic acid are cofactors of pyruvate dehydrogenase and α-ketoglutarate dehydrogenase that participate in decarboxylation and oxidation of their respective substrates. TPP consists of the vitamin thiamine, also known as vitamin B1, and pyrophosphate. The name thiamine was proposed by Robert R. Williams, who was the first to both determine the chemical structure of vitamin B1 and to synthesize it. Because he found using arbitrary letters (A, B, C···) to name vitamins confusing, he suggested the name based on the chemistry of the substance. The name thus stands for sulfur-containing vitamin, ́ = sulfur.21 Pyrophosphate was from the Greek theio (θεiο) named by Thomas Clark, who prepared it by heating sodium phosphate. As in the case of pyruvate, the prefix “pyro-” is derived from the Greek word meaning fire.22 Lipoic acid was first isolated from the liver as a compound, which very actively stimulated the growth of lactic acid bacteria (Lactococcus lactis, formerly Streptococcus lactis) in the absence of acetate and was required for pyruvate dehydrogenase activity in Streptococcus faecalis (renamed Enterococcus faecalis).23 The substance was named lipoic acid, from lipos ́ (λiπος) = fat, to refer both to the fact that it is an acidic compound highly soluble in fat solvents and that it is involved in the oxidative decarboxylation of pyruvate, which participates in the formation of acetate, the precursor of fatty acids.
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SUMMARY
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AUTHOR INFORMATION
Communication
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REFERENCES
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A significant part of the language of biochemistry is based on the trivial names of the biomolecules. For students, as well as for teachers, who rarely master Greek or Latin, most of these names are just words, the origin of which is far from intuitive. Compounds associated with the CAC, the etymology of whose names is reviewed here (see also Table 1), are among the ones that are “run in to” during the study of biochemistry the most often. Knowing the origins of these names helps both teachers and students by providing them with a new perspective on the subject.
Corresponding Author
*E-mail:
[email protected]. ORCID
Peter Polčic: 0000-0003-0341-7533 Notes
The author declares no competing financial interest. C
DOI: 10.1021/acs.jchemed.8b00059 J. Chem. Educ. XXXX, XXX, XXX−XXX
