biomolecules Review The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis Laura-Katharina Bertels, Lucía Fernández Murillo and Jürgen J. Heinisch * Department of Genetics, Faculty of Biology/Chemistry, University of Osnabrück, Barbarastrasse 11, D-49076 Osnabrück, Germany; [email protected] (L.-K.B.); [email protected] (L.F.M.) * Correspondence: [email protected] Abstract: The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6- phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the reversible transketolase and transaldolase reactions, which interchange PPP metabolites with glycolysis. While the oxidative branch is vital to cope with oxidative stress, the non-oxidative branch provides precursors for the synthesis of nucleic, fatty and aromatic amino acids. For glucose catabolism in the baker’s yeast Saccharomyces cerevisiae, where its components were first discovered and extensively studied, the PPP plays only a minor role. In contrast, PPP and glycolysis contribute almost equally to glucose degradation in other yeasts. We here summarize the data available for the PPP enzymes focusing on S. cerevisiae and Kluyveromyces lactis, and describe the phenotypes of gene deletions and the benefits of their overproduction and modification. Reference to other yeasts and to the importance of the PPP in their biotechnological and medical applications is briefly being included. We propose future studies on the PPP in K. lactis to be of special interest for basic science and as a host for the expression of human disease genes. Citation: Bertels, L.-K.; Fernández Murillo, L.; Heinisch, J.J. The Pentose Keywords: carbohydrate metabolism; oxidative stress; reduction power; bioethanol; cancer Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis. Biomolecules 2021, 11, 725. https:// doi.org/10.3390/biom11050725 1. Introduction For a long time investigations of central carbohydrate metabolism in yeast has raised Academic Editors: Grzegorz Janusz, comparatively little scientific interest. This has changed in the last few years with their Daniel Kracher and Anna Pawlik increasing relevance for novel biotechnological processes and the enormous potential of the new discipline of synthetic biology [1,2]. Moreover, although the wine, beer, and baker’s Received: 31 March 2021 yeast Saccharomyces cerevisiae holds a leading position not only in classical fermentations Accepted: 10 May 2021 Published: 12 May 2021 but also as a key model organism for eukaryotic cell biology [3,4], other “non-conventional” yeast species have been intensively studied as alternative microbial models and production organisms [5–7]. Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in In this context, we decided to give an overview of the role of the pentose phos- published maps and institutional affil- phate pathway, further abbreviated as PPP, and its constituting enzymes in yeast sugar iations. metabolism, as compared to glycolysis. Besides the best studied yeast S. cerevisiae, we will primarily concentrate on the milk yeast, Kluyveromyces lactis, for its close relationship and model character [8], but also refer to Candida albicans, for its importance as an opportunistic human pathogen [9,10], and other yeast species, whenever data are available. For a broader perspective, including the importance for human physiology, interested readers are referred Copyright: © 2021 by the authors. to excellent reviews on the PPP [11] and on yeast glycolysis [12,13]. Further reviews on the Licensee MDPI, Basel, Switzerland. This article is an open access article functions of the PPP in other fungi, plants, bacteria, the human immune system or the liver distributed under the terms and are also available [14–19]. conditions of the Creative Commons 2. Overview on the Reactions of the Pentose Phosphate Pathway (PPP) Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ The PPP is generally depicted with two branches (Figure1): (i) the oxidative, essen- 4.0/). tially irreversible part, owing its designation to the generation of NADPH in two of its key Biomolecules 2021, 11, 725. https://doi.org/10.3390/biom11050725 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 20 Biomolecules 2021, 112., Overview 725 on the Reactions of the Pentose Phosphate Pathway (PPP) 2 of 20 The PPP is generally depicted with two branches (Figure 1): (i) the oxidative, essen- tially irreversible part, owing its designation to the generation of NADPH in two of its key reactions,reactions, and (ii) the and (ii)non-oxidative, the non-oxidative, reversible reversible part, part, in inwhich which metabolites metabolites are are interconverted inter- converted by theby thetransaldolase transaldolase and and transketolas transketolasee reactions. reactions. The The latter alsoalso linklink thethe PPP PPP to to central central carbohydratecarbohydrate metabolism metabolism by byproducin producingg the the glycolytic glycolytic intermediatesintermediates fructose-6-phosphate fructose-6- phosphate andand glyceraldehyde-3-phosphate. glyceraldehyde-3-phosphate. Figure 1. OverviewFigure 1. Overview of the reactions of the of reactions the pentose of the phosphate pentose pathway phosphate (PPP) pathway and its connection(PPP) and its to glycolysisconnection and to al- coholic fermentation.glycolysis and Enzymes alcoholic are designatedfermentation. in bold Enzymes blue letters, are designated adopted fromin bold the blue nomenclature letters, adopted in Saccharomyces from cerevisiae. Wherethe nomenclature more than one in isozyme Saccharomyces operates cerevisiae in this yeast,. Where numbers more behind than one the isozyme three-letter operates code have in this been yeast, omitted. Enzymes markednumbers by behind a red asterisk the three-letter are encoded code by have only been one essentialomitted. gene Enzymes in the marked milk yeast by Kluyveromycesa red asterisk lactisare , i.e., deletions areencoded not viable. by One-headedonly one essentia arrowsl designategene in the physiologically milk yeast Kluyveromyces irreversible reactions, lactis, two-headedi.e., deletions arrows are not reversible ones. The oxidativeviable. One-headed part of the PPP arrows is shaded designate in blue, physiologica the non-oxidativelly irreversible part in green. reaction Abbreviationss, two-headed of metabolites arrows are: reversible ones. The oxidative part of the PPP is shaded in blue, the non-oxidative part in green. G-6-P = glucose-6-phosphate; F-6-P = fructose-6-phosphate; F-1,6-P2 = fructose-1,6-bisphosphate; GAP = glyceraldehyde- 3-phosphate;Abbreviations DHAP = dihydroxyacetone of metabolites phosphate; are: G-6-P 6-PGL= glucos = 6-phosphogluconolactone;e-6-phosphate; F-6-P = fructose-6-phosphate; 6-PGA = 6-phosphogluconate; F- Ribu-5-P =1,6-P ribulose-5-phosphate;2 = fructose-1,6-bisphosphate; Xylu-5-P = xylulose-5-phosphate; GAP = glyceraldehyde-3-phosphate; Ribo-5-P = ribose-5-phosphate; DHAP = Ery-4-Pdihydroxyace- = erythrose-4- tone phosphate; 6-PGL = 6-phosphogluconolactone; 6-PGA = 6-phosphogluconate; Ribu-5-P = phosphate; Sed-7-P = sedoheptulose-7-phosphate; Sed-1,7-P2 = sedoheptulose-1,7-bisphosphate. Enzyme/protein designa- tions are: Hxtribulose-5-phosphate; = hexose transporter; Xylu-5-P Hxk = hexokinase; = xylulose-5-phosph Pgi1 = phosphoglucoseate; Ribo-5-P isomerase; = ribose-5-phosphate; PFK = phosphofructokinase, Ery-4-P = written in capitalerythrose-4-phosphate; letters, because it is aSed-7-P heterooctameric = sedoheptulose-7-phosphate; enzyme formed by four α- Sed-1,7-P and four ß-subunits,2 = sedoheptulose-1,7- encoded by the genes PFK1 and PFK2bisphosphate.[20]; Fba1 =Enzyme/protein fructose-1,6-bisphosphate designations aldolase; are: Tpi1Hxt == triosephosphatehexose transporter; isomerase; Hxk = Tdh hexokinase; = glyceraldehyde- Pgi1 3-phosphate= phosphoglucose dehydrogenase (“triosephosphate isomerase; PFK dehydrogenase”);= phosphofructokinase, Pgk1 = written phosphoglycerate in capital kinase;letters, Gpm1because = phospho-it is a glycerate mutase;heterooctameric Eno = enolase; enzyme Pyk1 formed = pyruvate by four kinase; α- Pdcand =four pyruvate ß-subunits, decarboxylase; encoded Adh by =the alcohol genes dehydrogenase; PFK1 and Zwf1 = glucose-6-phosphatePFK2 [20]; Fba1 dehydrogenase= fructose-1,6-bisphosphate (“Zwischenferment”); aldola Solse; Tpi1 = phosphogluconolactonase = triosephosphate isomerase; (“suppressor Tdh of =los1-1 ”); Gnd = phosphogluconateglyceraldehyde-3-phosphate dehydrogenase; Rki1dehydrogenase = ribosephosphate (“triosephosphate ketol isomerase; dehydrogenase”); Rpe1 = ribulosephosphate Pgk1 = phos- epimerase; Tkl = transketolase;phoglycerate Tal =kinase; transaldolase; Gpm1 = Shb17 phosphoglycerate = sedoheptulose-1,7-bisphosphatase; mutase; Eno = enolase; PDH Pyk1 = = pyruvate pyruvate dehydrogenase kinase; complex; TCAPdc == tricarboxylicpyruvate decarboxylase; acid cycle. Adh = alcohol dehydrogenase; Zwf1 = glucose-6-phosphate dehy- drogenase (“Zwischenferment”); Sol = phosphogluconolactonase (“suppressor of los1-1”); Gnd = phosphogluconate dehydrogenasBoth the PPPe; and Rki1 the = EMP ribosephosphate (Embden–Meyerhof–Parnas ketol isomerase; pathway, Rpe1 = ribu- or simply glycolysis) losephosphate epimerase;are ancient Tkl biological = transketolase; processes Tal