Subsystem: Acetoin, butanediol metabolism

This subsystem's description is:

I. Synthesis of acetoin and butanediol (acetoin, butanediol fermentation)

In some bacteria, pyruvate can be channeled via alpha-acetolactate and acetoin into the neutral compound 2,3-butanediol, the production of which is induced when oxygen is limited and the pH is lowered. The metabolic function of the 2,3-butanediol pathway is believed to be that of preventing intracellular acidification by changing the metabolism from acid production to the formation of neutral compounds. In addition to controlling the pH, the butanediol pathway participates in the regulation of the NADH-NAD ratio. Large amounts of NAD are regenerated from NADH during glucose degradation, as acetoin is reduced to 2,3-butanediol. After glucose exhaustion, when NADH is not formed, this reaction is reversed, and extracellular 2,3-butanediol acts as a reservoir of reducing equivalents. Three enzymes are involved in the 2,3-butanediol pathway:
Acetolactate synthase, catabolic (EC catalyses formation of acetolactate from pyruvate. Acetolactate is decarboxylated by Alpha-acetolactate decarboxylase (ALDC) into acetoin, which in turn is reduced in a reversible reaction into 2,3- butanediol by 2,3-butanediol dehydrogenase (BDH). In some species this enzyme is also involved in irreversible reduction of diacetyl to acetoin [acetoin (diacetyl) reductase].
Diacetyl, a side product of this pathway, is produced nonenzymatically by oxidative decarboxylation of a-acetolactate (Boumerdassi et al., 1996). Diacetyl has a strong, buttery flavor and yellow color and is essential at low concentrations in many dairy products, such as butter, butter- milk, and fresh cheeses. It is also considered to be the most important off-flavor in the brewing process and in the wine industry (Hugenholtz et al., 2000).

Note: In addition to catabolic Acetolactate synthase (ALS_c), anabolic Acetolactate synthase, involved in the valine-leucine and isoleucine pathways (see SS: Branched-Chain Amino Acid Biosynthesis) has been included in this SS as an auxiliary role (to help disambiguate different types of Acetolactate synthases). In addition, other TPP –dependent enzymes paralogous to ALS have been included – for the same reason (they are grouped into Subset “Auxilary roles” together with several hypothetical genes they often co-localize with).

II. Acetoin, butanediol utilization

Acetoin can be (re)utilized during stationary phase when other carbon sources have been depleted by many bacterial species. The key reaction of the fermentative breakdown of acetoin (3-hydroxy-2-butanone) is the thiamine PPi (TPP)-, coenzyme A-, and NAD-dependent cleavage of acetoin into acetaldehyde and acetyl coenzyme A, which is catalysed by the acetoin dehydrogenase (AcDH) enzyme system (Huang et al., 1999). In addition to the structural genes of the acetoin dehydrogenase (acoABCL), acoX (encoding a protein of unknown function), and acoR (encoding a putative regulatory protein) are often localized in the same cluster. Utilization of 2,3-butanediol requires in addition 2,3-butanediol dehydrogenase, which feeds the substrate to the acetoin dehydrogenase enzyme system. Existence of enzymes other then AcDH utilizing acetoin can be predicted in yeast (see “Open Problems” below)

III. Stereo-specificity of 2,3-butanediol dehydrogenase

Stereo-specificity of 2,3-butanediol dehydrogenase is an industrially important issue. The levoisomer of 2,3-butanediol is particularly sought after as an antifreeze agent due to its low freezing point. The compound can also be applied to the production of butadiene and liquid fuel (Voloch et al., 1984). It is a rather complex issue, however, and almost impossible to assert based on protein sequence alone.
All three stereoisomers of 2,3- butanediol can be produced by various microorganisms (Klebsiella pneumoniae, Bacillus subtilis, Serratia marcescens, Aeromonas hydrophila, Enterobacter aerogenes, K. terrigena, ets.). Depending on the microorganism and the conditions of grown, the ratio of 2,3-butanediol (2,3-BD) stereoisomers can vary dramatically. It is believed, that (R)-acetoine is largely produced from pyruvate via alpha-acetolactate synthase and acetolactate decarboxylase pathway (L-acetoin production is rare and can be catalyzed, for example, by acetoin racemase postulated to exist in some organisms – role NOT associated with any sequence yet). Taylor and Juni (1960) proposed a model for the formation of all 2,3-BD stereoisomers based on the existence of only three enzymes: an acetoin racemase, L(+)-BD dehydrogenase and D(-)-BD dehydrogenase. In this model dehydrogenases are considered to be non-specific with respect to acetoin stereoisomers. That is, they would accept either acetoin isomer as substrate, but the reaction product would still be dependent on the acetoin isomer reduced. For example, the L-( +)-dehydrogenase would reduce L-(+)-acetoin to L- (+)-2,3-BD and D-( -)-acetoin to meso-2,3-BD. This assumption seems to be correct for some 2,3-BDHs studied so far (e.g. yeast BDH recognizes both R-acetoin and S-acetoin, yielding R-carbon in both cases (Gonzales et al., 2000)) but does NOT hold for others (e.g. Klebsiella pneumoniae BDH seems to recognize only R-acetoin (Ui et all., 1999), yielding R-alcohol)
The ability of the same enzyme to catalyze the reverse reaction of 2,3–butanediol oxidation to acetoin adds to the complexity. Although the stereo-specificity for the R- and/or S-carbon holds, substrate preference (meso-BD vs R,R-2,3-BD) can differ, affecting the resultant product mix (Voloch et al., 1984).
In this SS an attempt was made to project stereo-specificity from well studied 2,3-BDHs (only three available) to all sequenced orthologs based on phylogenetic trees. Understandably, mistakes are unavoidable and actual stereospecificity of individual enzymes can differ! Assertions here have been based on the experimentally established stereo-specificity of the following enzymes:

1. Saccharomyces cerevisiae YAL060W gene product (Gonzales et al., 2000): 2,3-butanediol dehydrogenase, R-alcohol forming, (R)- and (S)-acetoin-specific (EC

2. Klebsiella pneumoniae IAM 1063 enzyme (Ui, et al., 1998, 1999, 2004): 2,3-butanediol dehydrogenase, S-alcohol forming, (R)-acetoin-specific (EC

3. Brevibacterium saccharolyticum (Ui, et al., 2004): 2,3-butanediol dehydrogenase, S-alcohol forming, (S)-acetoin-specific (EC

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