alcohol dehydrogenases: identification and names for gene families

Plant Molecular Biology Reporter17: 333–350, 1999.© 2000Kluwer Academic Publishers. Printed in the Netherlands.

Commentary

Alcohol Dehydrogenases: Identification and Names forGene Families

THEODORE CHASE, JR.∗Department of Biochemistry and Microbiology, 76 Lipman Drive, Cook College,Rutgers University, New Brunswick, NJ 08901-8525, USA

Abstract. Plant gene products that have been described as ‘alcohol dehydrogenases’ aresurveyed and related to their CPGN nomenclature. Most are Zn-dependent medium chaindehydrogenases, including ‘classical’ alcohol dehydrogenase (Adh1), glutathione-dependentformaldehyde dehydrogenase (Fdh1), cinnamyl alcohol dehydrogenase (Cad2), and benzyl al-cohol dehydrogenase (Bad1). Plant gene products belonging to the short-chain dehydrogenaseclass should not be called alcohol dehydrogenases unless such activity is shown.

Key words: alcohol dehydrogenase, cinnamyl alcohol dehydrogenase, formaldehyde dehy-drogenase, short chain dehydrogenase

Abbreviations: Adh, alcohol dehydrogenase; Bad, benzyl alcohol dehydrogenase; Cad, cin-namyl alcohol dehydrogenase; Fdh, glutathione-dependent formaldehyde dehydrogenase.

Introduction

From the standpoints of structure, genetics, and enzymology the name ‘alco-hol dehydrogenase’ is somewhat imprecise, since it can refer to as substrateseither ethanol and similar alkanols, or any compound with ‘alcohol’ in thecommon name, such as cinnamyl alcohol. Enzymes corresponding to at least25 EC numbers could be called ‘alcohol dehydrogenases’, including NAD+-,NADP+-, and pyrroloquinoline-quinone-using enzymes. Many of these en-zymes will indeed oxidize ethanol, but with unphysiologically largeKm. Assummarized in Table I, true alcohol dehydrogenases, enzymes with maxi-mal activity on ethanol or other small alkanols, are type species for at leastfour unrelated gene groups. This array should warn investigators of the di-verse genotypes that have been described as ‘alcohol dehydrogenases’, and

∗Author for correspondence. e-mail: [email protected]; fax: (732)932-8965;ph: (732)932-9763, ext. 313.

334 Theodore Chase, Jr.

are often specified as such in data bases, even though no enzymatic activityhas been defined. In particular, while the type species for short-chain dehy-drogenases is the alcohol dehydrogenase ofDrosophila melanogaster, thisremains the only ethanol-active member of the group (of 55 sequences, 41of known biochemical function), and even it is more active on secondaryalcohols than on ethanol. Sequences in this class should, therefore, be re-ferred to asshort-chain dehydrogenases, not alcohol dehydrogenases, unlesssuch activity is specifically found. Enzymatic activity has been specified foronly a few plant gene products of this class (3-oxoacyl-acyl carrier proteinreductase, tropinone reductases).

Alcohol Dehydrogenases in Plants

Happily, most alcohol dehydrogenases that have been characterized at thegene level in plants belong to three groups of dimeric, zinc-containing en-zymes (Table 2): NAD+-dependent ‘classical’ alcohol dehydrogenases activeon ethanol (EC 1.1.1.1); NADP+-dependent cinnamyl alcohol dehydroge-nases active in lignin biosynthesis (EC 1.1.1.195); and ‘formaldehyde-activeclass III alcohol dehydrogenases’= S-hydroxymethylglutathione dehydroge-nases (EC 1.2.1.1; Shafqat et al., 1996) (Table 2). Other alcohol dehydroge-nases have been noted in plants, such as NADP-dependent aromatic (benzyl)alcohol dehydrogenase (EC 1.1.1.91) (Somssich et al., 1996) and terpenoidalcohol dehydrogenase (Davies et al., 1973). These are distinct from cinnamylalcohol dehydrogenase 2, which is not active on benzyl alcohol or terpenoidalcohols. Cinnamyl alcohol dehydrogenase 1 has now been shown to act on anumber of substituted benzaldehydes (Goffner et al., 1998) and is unrelatedto Cad2.

A few representatives of the short-chain dehydrogenase class have beencloned from plant sources, but the molecular functions of only a few areknown, and these are distinct from alcohol dehydrogenase.

Gene Families Encoding Alcohol Dehydrogenases in Plants

The Commission on Plant Gene Nomenclature has recommended guidelinesfor naming sequenced plant genes (Price et al., 1996, updated at http://mbcl-server.rutgers.edu/CPGN/Guide.html). Genes that encode products with sim-ilar sequences are placed in plant-wide gene families identified by productfamily numbers (PFNos.). Those with identifying function are named withthree or four letters and a number (e.g.,Adh1). A sequence-defined productfamily (one PFNo.) may include more than one function-defined gene family

Alco

hold

ehyd

rogenase

s335

Table 1. Classes of alcohol dehydrogenases

Class Characteristics, Exemplars, EC numbers References

Short chain ≈250 residues:DrosophilaAdh (EC 1.1.1.1), steroid Jörnvall et al., 1995

oxidoreductases (EC 1.1.1.51, etc.)

Medium chain ≈375 residues Jörnvall et al., 1987;

Persson et al., 1994

Zn-containing dimeric formsa contain a second, structural (non-catalytic) Zn:

horse-liver alcohol dehydrogenase (EC 1.1.1.1),

cinnamyl alcohol dehydrogenase (EC 1.1.1.195)

tetrameric forms Adh ofS. cerevisiae(EC 1.1.1.1), sorbitol

dehydrogenase of sheep (EC 1.1.1.14)

non-Zn-containing quinone reductases/β-crystallins (EC 1.6.5.5), enoyl Borras et al., 1989

reductases (EC 1.3.1.10)

Long chain 600–750 residues, bacterial ethanol dehydrogenases, Inoue et al., 1989

e.g. ofAcetobacter aceti; pyrroloquinoline quinone

as cofactor (EC 1.1.99.8)

Fe-activated 1,2-propanediol dehydrogenase ofE. coli (EC 1.1.1.77) Sridhara et al., 1969

Adh2 of Zymomonas mobilis(EC 1.1.1.1); Scopes, 1983;

Conway et al., 1987;

Conway and Ingram, 1989

Adh IV of S. cerevisiae Williamson and Paquin, 1987

aDimeric dehydrogenases have been separated further into at least six classes (see Shafqat et al., 1996), including ‘formaldehyde-active class IIIalcohol dehydrogenases’, with members from bacteria to man, originally described asχχ alcohol dehydrogenase but most active on the adductS-hydroxymethylglutathione (EC 1.2.1.1), though alcohols such asn-octanol are substrates with much higherKm values.


Table 2. Principal classes of alcohol dehydrogenases in plants

Class and Subclass EC No. PF No. Gene family

Alcohol (ethanol) dehydrogenasea 1.1.1.1 1140 Adh1; Adh0b

Adh (formaldehyde-active) class III= 1.2.1.1 1140 Fdh1

hydroxymethylglutathione dehydrogenasea

Cinnamyl alcohol dehydrogenasea 1.1.1.195 1141 Cad2

Aromaticc Adha 1.1.1.91 1141 Bad1

Aromaticd Adh 1.1.1.91 2995 Cad1

Short-chain dehydrogenases:

Tropinone reductases 1.1.1.206, 2956 Trr1

1.1.1.236 2957 Trr2

Tropinone reductase-related 2957 Trr0

β-Ketoacyl-ACP reductase 1.1.1.212 2960 [Ker1]e

tasselseed2gene product, etc. 2955

TFHP-1 proteinf , etc. 2961

Picea abies‘short-chain dehydrogenase’ 2967

aMedium-chain, presumably Zn-containing and dimeric, since their sequences contain theZn-binding residues.

bMore distantly related, heterogeneous genes; functions of gene products not known.cActive on benzyl alcohols; defense related.dMonomeric, some with activity also on coniferyl alcohol (EC 1.1.1.194), related todihydroflavonol-4-reductases and cinnamoyl CoA reductases.

eDesignation suggested by Penny von Wettstein-Knowles, Fatty Acid Biosynthesis WorkingGroup;FabG in bacteria.

fTobacco protein binding to a positive control element of an introduced horsradishperoxidase geneprxC2(Kawaoka et al., 1994).

(see Table 2). Genes in individual plant species are identified by three fields:an abbreviation of the plant species, the gene family, and a member numberthat corresponds to membership in multigene families within the species (e.g.,ZEAma;Adh1;2identifies the second member of theAdh1 gene family inmaize). Table 3 lists names for the plant-wide families of genes encodingalcohol dehydrogenases and related enzymes. These have with one excep-tion (3-oxoacyl-acylcarrier protein reductase) been approved by the CPGN.Names have been assigned only when enzymatic function is known, thoughthis has not necessarily been demonstrated for all members of a sequencegroup.

Alcohol dehydrogenases 337

Table 3. Representative members of gene families

Gene Family Species Representative members

GenBank/EMBL Swiss-Prot

AC AC

Adh1 Arabidopsis thaliana X77943 P06525

Zea mays X00580 P00333

Adh0 Solanum tuberosum X92179 Q43169

Lycopersicon esculentum S75487 Q41241

Bad1 Arabidopsis thaliana X67816 Q02971

Petroselinum crispum X67817 P42754

Cad1 Eucalyptus gunnii X88797 O04391

Cad2 Eucalyptus gunnii X65631 P31655

Arabidopsis thaliana Z31715 P48523

Fdh1 Arabidopsis thaliana X82647 Q43384

Zea mays Y11029 P93629

Trr1 Datura stramonium L20473 P50162

Trr2 Datura stramonium L20474 P50163

Hyoscyamus niger L20485 P50164

[Ker1a] Cuphea lanceolata X64566 P28643

Arabidopsis thaliana X64464 P33207

aDesignation suggested by Penny von Wettstein-Knowles, Fatty Acid Biosyn-thesis Working Group; FabG in bacteria.

Complete sets of all of these gene families, alignments, consensus sequences,etc. are listed on the CPGN Web site at http://mbclserver.rutgers.edu/CPGN/

Adh1

There is a surprisingly high sequence identity among the classical, NAD+-dependentAdhacross gymnosperms and angiosperms:≥71% at the nucleotidelevel, and≥79% at the amino acid level (Kinlaw et al., 1990).

Within monocots – mostly the grasses: maize, barley, wheat, rice, pearlmillet–Adh1 genes fall into two subgroups of isozymes, traditionally de-scribed as ‘Adh1’ and ‘Adh2’ (Dennis et al., 1984, 1985). The differences,78 to 82% identity of nucleotide sequence between subgroups compared to84 to 86% within subgroups, are, however, too small to justify assigning themto separate gene families. The two sets of gene products form heterodimers.

While all the dicot sequences are more similar to each other than to anymonocot sequence, and the gymnosperm sequences are a third, equidistantgroup (Yokoyama and Harry, 1993), the sequences do not show similarlycoherent subfamilies. Even within the Solanaceæ, which typically show two


enzymes, hypoxia-induced and anther- or anther- and seed-specific Adhs, noconsistent amino acid substitutions in one isozyme vs. the other have beendiscerned among petunia, potato, and tomato. A typical example is tomato,with one isozyme, termed ‘Adh1’ by Tanksley and Jones (1981), that is ex-pressed constitutively in pollen and mature seeds, and a second, ‘Adh2,’ thatis induced by hypoxia. Both such function-defined Adh have been sequencedin petunia: P25141 in Fig. 2= ‘Adh1’, Q07321= ‘Adh2’.

The overall similarities, however, are such that all of these genes shouldbe included in a single, plant-wide family. We propose the nameAdh1.

Adh0

Two sets of genes are closely related toAdh1, but with distinctly divergentsequences. No enzymatic activity has been defined for any of their products,and it seems premature to designate them specifically. We therefore call themAdh0as a tentative term until more is known.

A sequence (X92179) distantly related toAdh1has been described fromSolanum tuberosum.It was expressed in the pistil, though the Adh activitydemonstrated there using 10% ethanol as substrate was not necessarily due tothe product of this gene (Van Eldik et al., 1997).

Two tandem open reading frames (S75487, S75488) reported fromLyco-persicon esculentum(Ingersoll et al., 1994; termed by themAdh3) are 93.8%identical to each other at the nucleotide level but only 68–69% identicalto plant Adh1 at the nucleotide sequence and only 56–59% at the amino-acid level. At least one of these is transcribed and the mRNA processed, butwhether the protein is expressed, much less what its enzymatic activity is, isnot known. The sequences of putative products of these genes are shown inFigure 1, along with representative Adh1 (one each from monocots, dicotsand gymnosperms) and Fdh1 (see below.)

Two other even less known genes from arabidopsis, one fromZea maysand one fromGossypium hirsutum, have also been placed in this category.

Related Genes and Enzymes

There are a number of divergent enzymes that have been called ‘alcohol de-hydrogenase’ but which have a primary substrate other than ethanol. Some ofthe animal enzymes will oxidase ethanol weakly or with very highKm; othersare completely inactive on ethanol.


Figure 1.


Figure 1. Alignment of sequences of representative Adh1 (Zea maysAdh1.1, Arabidopsisthaliana Adh1, Pinus banksianaAdhC3), Fdh1 ofOryza sativa, Zea mays, Arabidopsisthaliana, andPisum sativum, and outlying sequences (Adh0) fromLycopersicon esculentum(‘Adh3’) andSolanum tuberosum(PF No. 1140).

Fdh1

Formaldehyde dehydrogenase, also known as ‘class III alcohol dehydroge-nase,’ acts on hydroxymethylglutathione, the formaldehyde adduct of glu-tathione. It is inactive on ethanol and weakly active onn-octanol. The enzymewas purified as an auxin-binding protein fromZea mays(Sugaya and Sakai,1995); purified fromPisum sativum, and the protein sequenced (Shafqat et al.,1996); purified and characterized from arabidopsis (Martínez et al., 1996),and the gene cloned and sequenced from arabidopsis andOryza sativa(Dol-ferus et al., 1997). Shafqat et al. considered this gene to be ancestral to plantand animalAdh through separate gene duplications, and Dolferus et al. ex-tended this by showing that the ethanol and formaldehyde dehydrogenases ofplants have eight introns in the same locations, different from their locationsin humanAdh1.With Dolferus et al., we abbreviate this gene family asFdh1,to emphasize that it is not active on ethanol, not an ‘alcohol dehydrogenase’in terms of substrate specifity, and that it appears to be a plant-wide family.

The relationships of Fdh1, a wider range of Adh1, and Adh0 are presentedin Figure 2. All these are included in the gene product family (PFNo.) 1140,but the Adh0 sequences are relatively distant from Adh1 and Fdh1.

Cad2

The cinnamyl alcohol dehydrogenases (historically abbreviated Cad or CAD)use NADPH to reduce methoxylated cinnamaldehydes to the corresponding


Figure 2. Dendrogram of sequences in PF No. 1140 (Adh1, Fdh1, Adh0).

alcohols (EC 1.1.1.195). In soybean (Wyrambik and Grisebach, 1975),Euca-lyptus gunnii(Goffner et al., 1992) andPhaseolus vulgaris(Grima-Pettenatiet al., 1994), two isozymes have been observed, Cad1, which is monomeric(mol. mass 35 kDa) and active primarily or exclusively on coniferaldehydeamong the cinnamaldehydes, but with a high (25–70µM) Km, and Cad2,which is dimeric (monomer mol. mass 38 kDa), active on various cinnamalde-hydes, though best on coniferaldehyde, with a low (µM) Km. All the cin-namyl alcohol dehydrogenase genes cloned and sequenced through 1997 en-code Cad2 (explicitly in the case ofE. gunnii: Grima-Pettenati et al., 1993)and therefore are designatedCad2; sequence identities at the amino acid levelare 75 to 80% among angiosperms, 67 to 70% to gymnosperms. Homology toAdh1is≈20%, and≈25% to yeast Adh; residues critical to Adh catalysis areconserved. A supposed bean cinnamyl alcohol dehydrogenase cDNA (Walteret al., 1988) has since been concluded to represent a malic enzyme (Walteret al., 1990). It does not resembleCad2.


Bad1

A ‘novel plant defense gene’ found in arabidopsis and parsley, calledEli3(Kiedrowski et al., 1992), is≈50% identical toCad2and has the expectedcritical residues for catalysis. The arabidopsis protein Eli3-2 has now beenshown to have NADP+-dependent benzyl alcohol dehydrogenase activity (EC1.1.1.91), though it is primarily active as a benzaldehyde reductase. FollowingSomssich et al. (1996), we suggest the nameBad1for the gene family. Similarsequences have been reported fromStylosanthes humilis(Q43137, Q43138)andMesembryanthemum crystallinum(P93257), but the gene products are asyet uncharacterized. We tentatively include them inBad1.

While the Bad1 and Cad2 sequences are generally similar, some differ-ences can be noted, though the Bad1 sequences are less consistent. See,in Figure 3, residues 25–32, 115–127, 183–190, 249–255, 270–278, 292–300, 323–337 (numbering ofE. gunnii Cad2). The gymnosperm CAD2 se-quences are generally less similar to those of angiosperms, and frequentlymore similar to Bad1.

A ‘cinnamyl alcohol dehydrogenase homolog’ gene from arabidopsis(P42734: Somers et al., 1995), with 50% identity to bothCad2 and Bad1and different from arabidopsisCad2 (Baucher et al., 1995) is here listedwith Bad1, though its product’s activity has not been determined. A closelyrelated sequence (Q38707) from celery (Apium graveolens), 83% identical toparsley and arabidopsis Bad1, was identified as a NAD-dependent mannitoldehydrogenase (Williamson et al., 1995); thus with more study Bad1 may befurther subdivided.

The relationships among these sequences are shown in Figure 4. Here it isevident that the Bad1 sequences group separately from the Cad2.

Cad1

Cad1 of Eucalyptus gunniihas now been cloned and sequenced (Goffneret al., 1998); it proves to be unrelated toCad2, belonging to a completely dif-ferent superfamily, the 3β-hydroxysteroid dehydrogenases/dihydroflavonol-4-reductases (Baker and Blasco, 1992). It most closely resembles cinnamoyl-CoA reductase, the previous enzyme in the lignin biosynthesis pathway. Ithas broader specificity than Cad2, acting on (with increasingKm values)3-methoxybenzaldehyde, hydrocinnamaldehyde, benzaldehyde, cinnamalde-hyde, crotonaldehyde, and even acetaldehyde (Km = 1.3 mM), and is termedby the authors an aromatic alcohol dehydrogenase. They note homology withpeptide sequences of atypical Cad enzymes inPhaseolusandTriticum. Sim-ilar gene sequences have been reported fromMalus domesticaand Vignaunguiculata, and an NADPH-dependent aldehyde reductase reducing the fun-


Figure 3.

gal toxin eutypine (4-hydroxy-3(3-methyl-3-buten-1-ynyl)benzaldehyde) hasnow been isolated and cloned fromVigna radiata(Phaseolus aureus) (Guil-lén et al., 1998). Its sequence is 86.8% identical to the product of the drought-induced geneCPRD14of Vigna unguiculata, 71.7% identical to Cad1 ofE. gunnii. It has wide activity on substituted benzaldehydes, cinnamaldehy-des, and even decanal, thoughKm/Vmax is highest for eutypine. ThusCad1is a second gene family of aromatic alcohol dehydrogenases/aldehyde re-ductases, distinguished fromBad1by having gene products with activity oncinnamaldehydes as well as benzaldehydes.


Figure 3. Alignment of PFNo. 1141 sequences: Cad2 ofPicea abies, Pinus tæda, Eucalyptusgunnii, Nicotiana tabacum, Medicago sativa, Arabidopsis thaliana, andZea mays, and se-quences classed as Bad1 fromArabidopsis thaliana(2; Q02972 = ‘Eli3’),Stylosanthes humilis(2), Apium graveolens, andPetroselinum crispum.

A group of open reading frames from the arabidopsis sequencing project(O80531, O80532, O80533, O80534) are somewhat less similar to Cad1. TheCad1 mentioned above and a representative of these arabidopsis sequencesare compared in Figure 5.

Genes Related to ‘Short-Chain Dehydrogenases’

Short-chain dehydrogenases – other than the enzyme inD. melanogasterandother insects – are not active with ethanol; their true substrates are more likelyto be secondary alcohols or steroids. Bauer et al. (1993) described a sprucecDNA clone as ‘encoding a novel short-chain alcohol dehydrogenase’ onthe basis of sequence similarity to the short-chain dehydrogenase/reductasegroup. Similarly, theTASSELSEED2(Ts2) gene of maize, which when mu-


Figure 4. Dendrogram of Bad1 and Cad2 sequences.

tated results in a feminized tassel, has been cloned (DeLong et al., 1993),and its sequence resembles short-chain dehydrogenases (41% identical toComamonas testosteroni3-β-hydroxysteroid dehydrogenase, EC 1.1.1.51).Related cDNAs with 33 to 39% amino-acid identity toTs2have been clonedfrom Lycopersicon esculentum(Jacobsen and Olszewski, 1996) andSilenelatifolia, the former selected as a gibberellin-depressed mRNA. However, theenzymatic activity of these proteins, if any, has not been defined; consideringthe wide range of activities in this group, gene designations are premature.

Another set of plant genes in this group encode two tropinone reductases(EC 1.1.1.236) and a homolog fromDatura stramonium(Nakajima et al.,1993). The two enzymes, called Tr-1 and Tr-2, reduce the same substratebut with opposite stereospecificity; the genes are now designatedTrr1 andTrr2. The homolog is strongly expressed inD. stramonium, but the enzymaticreaction catalyzed has not been identified. It is placed in the unclassified cat-


Figure 5. Sequence comparison of Cad1 sequences (Cad1 ofEucalyptus gunniiandMalusdomesticus, eutypine reductase ofVigna radiata= Phaseolus aureus, drought-induced geneCPRD14 ofVigna unguiculata), and anArabidopsisgene of unknown function, representingfour open reading frames from the arabidopsis sequencing project.

egoryTrr0, along with two arabidopsis genes (Q42232, O49332) of unknownfunction.

Another homolog of the ‘short-chain dehydrogenases’ is 3-oxoacyl-ACPreductase (EC 1.1.1.100) ofCuphea lanceolata(Klein et al., 1992) and ara-bidopsis (Slabas et al., 1992). Genes encoding 3-oxoacyl-ACP reductase aredesignatedFabGin bacteria; the designationKer1has been suggested for thisplant gene, but not yet formally proposed (see footnote to Table 3).

The relationships among these gene sequences are shown in Figure 6.Interestingly, thePicea abiessequence Q08632 is most closely related toKer1. There is little overall sequence identity among these gene products,but a few elements are strongly conserved among them and in all short-chaindehydrogenases (Persson et al., 1991): the sequences ALVTGG(S/T)RGIG


Figure 6. Dendrogram of sequences of the short-chain dehydrogenase group (PFNos. 2955,2956, 2957, 2961, 2967, 4037). PFNo. 2955 comprises thetasselseed2sex determinationgene ofZea mays(DeLong et al., 1993), related genes inSilene latifoliaand Arabidopsisthaliana, and the gibberellin-repressed geneGAP3of Lycopersicon esculentum(Jacobsen andOlszewski, 1996). PFNo. 2956= Trr1 of Datura stramoniumandHyoscyamus niger, and PFNo. 2957= Trr2 of the same species. PFNo. 2961 comprisesTFHP-1, the gene for a tobaccoprotein binding to a positive control element of an introduced horsradish peroxidase geneprxC2 (Kawaoka et al., 1994) and a related gene ofIpomœa(O02465); however, sequenceP93697 ofVigna unguiculataseems more closely related to 2961 than to 2955, to which it hasbeen assigned. PFNo. 2967 is the ‘short chain dehydrogenase homolog’ ofPicea abies(Baueret al., 1993). PFNo. 4037= Trr0, genes ofDatura stramoniumand Arabidopsis thalianawhich are related toTrr1 andTrr2 but whose products’ function is unknown.

(res. 12–22 of Trr2; the first and fourth G are conserved in all short-chaindehydrogenases, and Cad1, otherwise dissimilar, has VCVTGASGYIA), IL-VNNAG (res. 90–97), YxaxK (res. 159–163; the Y and K are conserved in allshort-chain dehydrogenases), IrVNxVaP (res. 180–7; the V and P are stronglyconserved across short-chain dehydrogenases.)


Acknowledgements

This paper is dedicated to Dr Carl A. Price on the occasion of his retire-ment. I thank him for suggesting this study, for frequent discussions through-out the lengthy period of its preparation, and for preparation of the figures.Other members of the Adh working group reviewed and approved the genenomenclature assigned.

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alcohol dehydrogenases: identification and names for gene families

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