Glycolysis

TOC

Glycolysis

Chapter 14

DAN G. FRAENKEL

INTRODUCTION

The Embden-Meyerhof and pentose phosphate (pentose-P) pathways are the two trunk routes of intermediary sugar metabolism in enteric bacteria (Fig. 1). A third route, the Entner-Doudoroff pathway, is also mentioned, as are some of the connections (Fig. 2) with carboxylic acid pathways. The text mainly considers function, and there is a final section on general problems. Table 1 lists some key or recent papers on the genetics, enzymology, and molecular biology of the individual reactions.

Fig. 1Glycolysis. Where applicable, all compounds are D-configuration. Gene symbols are those used (or, in parentheses, suggested) for E. coli. The trunk route is indicated by heavy arrows. Other reactions may be peripheral, inducible, gluconeogenic, etc. (see the text).

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Fig. 2Reactions around pyruvate. Gene symbols are as in Fig. 1.

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Table 1Some referencesa

EMBDEN-MEYERHOF PATHWAY

Glucokinase and Phosphoglucomutase

Although the phosphoenolpyruvate (PEP) phosphotransferase system (see chapter 75) is the usual route of glucose uptake and phosphorylation, enteric bacteria also contain a glucokinase (glk). The normal role of this enzyme is unclear; it might act on glucose generated internally (e.g., from lactose). The slow growth on glucose of mutants defective in phosphotransferase components depends on glk, since its further loss then causes almost complete inability to grow on glucose (57, 83). The slow growth on glucose of phosphofructokinase (pfkA) mutants also depends on glucokinase (174). In a wild-type background, glk mutants grow almost normally on glucose (57).

Catabolism of galactose and maltose involves formation of glucose 1-phosphate (glucose-1-P), which is converted to glucose-6-P by phosphoglucomutase (pgm). In growth on other carbon sources, the same reaction is used biosynthetically to make glucose-1-P (and hence UDP-glucose). pgm mutants are impaired on galactose and stain blue with iodine (3, 142).

Phosphoglucose Isomerase and Phosphomannose Isomerase

The interconversion of glucose-6-P and fructose-6-P is catalyzed by phosphoglucose isomerase. Mutants (pgi) grow slowly on glucose using the pentose-P pathway (Fig. 1), with oxidative formation of pentose-P from glucose-6-P and with nonoxidative reactions yielding fructose-6-P and glyceraldehyde-3-P (86). Phosphoglucose isomerase is needed for synthesis of glucose-6-P in growth on substances that do not provide it by catabolism (glycerol, gluconate, etc.), but growth is adequate because glucose-6-P and derivatives are apparently not essential, as shown by lipopolysaccharide analysis (87), DNA glucosylation (111), or acid hydrolyzable glucose content (207). Normal location of some phosphoglucose isomerase to the periplasm was reported (91).

Phosphomannose isomerase (manA, pmi), like phosphoglucomutase, is used in both sugar catabolism (growth on mannose) and polysaccharide synthesis. Mutants lacking the isomerase are blocked in growth on mannose and are defective in mannose-containing polysaccharides (144, 175).

Phosphofructokinase (Fructose-6-P 1-Kinase) and Fructose-1,6-Bisphosphatase

The main phosphofructokinase of Escherichia coli, Pfk-1, is an allosteric enzyme activated by nucleoside diphosphates and inhibited by PEP (26), and it has been a major subject of structural and kinetic studies. pfkA mutants are impaired in their growth on substances catabolized via fructose-6-P (174, 206).

E. coli K-12 also has a minor phosphofructokinase activity (ca. 10% of the total), Pfk-2, encoded by pfkB. This activity is needed for the residual growth of pfkA mutants but has unknown function in pfkA ⁺ strains. The pfkB1 mutation, which suppresses the glucose negativity of a pfkA mutant, increases the expression of Pfk-2 by ca. 25-fold (8), and is a point mutation in the promoter (58). Originally thought to be nonallosteric, Pfk-2 was later shown (unlike Pfk-1) to be inhibited by ATP (133). Strains with high levels of a mutant form, Pfk-2*, insensitive to ATP inhibition (35, 104), are impaired in growth on gluconeogenic substances but slightly improved in growth on sugars (60). Deregulated conversion of fructose-6-P to fructose-1,6-P₂, observed in an in vitro model (203), might contribute to this phenotype, but the expected futile cycle was not detected in vivo (62).

Fructose-1,6-bisphosphatase (fbp) is used to form fructose-6-P from fructose-1,6-P₂ in growth on substances such as glycerol, succinate, and acetate; fbp mutants fail to grow on those carbon sources (85). The constitutive enzyme is sensitive to inhibition by AMP (11). A mutant strain with a normal amount of AMP-insensitive enzyme was not clearly impaired in growth (183).

Fructose-1,6-P₂ Aldolase

The (main) enzyme splitting fructose-1,6-P₂ to dihydroxyacetone-P and glyceraldehyde-3-P is a metal-dependent class II aldolase (fbaA) (17). A low level of phosphate modification was observed (10). fbaA mutants are unable to grow on sugars and sugar derivatives but still grow on substances such as glycerol or succinate. The most thoroughly studied mutant was temperature sensitive (27, 28, 186, 187), but nonconditional mutants have been reported (52, 121). Growth was inhibited by substances that provided fructose-1,6-P₂, and secondary blocks restored growth (e.g., gnd for growth on gluconate [181]).

Growth of fbaA mutants on glycerol and other substances requires the formation of fructose-1,6-P₂ from triose-P, perhaps employing a minor aldolase activity still found in the mutants (52); a class I (Schiff base-forming) aldolase has been characterized from the lactate-grown Crookes strain of E. coli (16). Physical differences in aldolase, depending on aeration, were observed (68).

Triose-P Isomerase and the Methylglyoxal Pathway

Triose-P isomerase (encoded by tpi) interconverts dihydroxyacetone-P and glyceraldehyde-3-P, and mutants are unable to grow on sugars, glycerol, or succinate alone but grow on succinate and other substances entering metabolism after the block if appropriately supplemented (6, 121). Such strains are very sensitive to accumulation of dihydroxyacetone-P, which is related to its conversion (117) to the bactericidal agent methylglyoxal (54). Although there is a glyoxalase that converts methylglyoxal to d-lactate, and thus a pathway for dihydroxyacetone-P dissimilation, it has low capacity and is insufficient to prevent methylglyoxal toxicity in the tpi mutant (54).

There are other cases in which excess dihydroxyacetone-P causes toxic levels of methylglyoxal (1, 90, 147), and the fact of a constitutive methylglyoxal synthase seems surprising. Hopper and Cooper (117) have speculated that inhibition by P_i might relate to a normal function for the enzyme under conditions of limited phosphate, in a sequence bypassing the lower portion (phosphate requiring) of the glycolytic pathway. Mutants with elevated glyoxalase could grow on 1 mM methylglyoxal (90). Methylglyoxal has been reviewed (53).

From Glyceraldehyde-3-P to PEP

For the conversion of glyceraldehyde-3-P to PEP, the sequence of reactions is glyceraldehyde-3-P dehydrogenase (gapA), phosphoglycerate kinase (pgk), phosphoglycerate mutase (gpm), and enolase (eno). A mutational block would be expected to prevent growth on sugars or other materials entering the pathway above the block (glucose or glycerol) or below it (succinate or pyruvate), and gap, pgk, and eno mutants were obtained as glycerol negative, succinate negative, and glycerol plus succinate positive (114, 120, 121). For these three steps, at least, single enzymes may catalyze the reaction in both directions; phosphoglycerate mutase mutants have not yet been reported. Expression of gapA is complex (43). A gap-like open reading frame in the pgk-fbaA cluster (5), which has figured in discussions of phylogeny, encodes an enzyme of vitamin B₆ synthesis (217a). Enolase is a phosphoprotein (64).

A thorough study of the gapA, pgk, and eno mutants (121) reported metabolite accumulations, some nutritional differences between the mutants, and the complications of their sensitivity to sugars.

Metabolism of PEP and Pyruvate

Figure 2 shows some of the complexities of the PEP and pyruvate metabolism pathways (see also chapter 18 and reference 45). There are two pyruvate kinase isoenzymes, Pyk-I or Pyk-F, and Pyk-II or Pyk-A. They differ kinetically, Pyk-F being activated by fructose-1,6-P₂ (29, 209) and Pyk-A being activated by AMP and other metabolites (210), as well as structurally (143) and in expression (132, 135). Double mutants are impaired on sugars other than substrates of the phosphotransferase system, in which pyruvate formation during uptake can bypass the block; mutants lacking a single isozyme grow well (96, 97, 164a).

The route from sugars to the dicarboxylic acids involves PEP carboxylase ( ppc) and produces oxalacetate. Oxalacetate is the precursor of other intermediates of the tricarboxylic acid cycle and of major families of biosynthetic products. ppc mutants are auxotrophic for a dicarboxylic acid such as succinate (7, 199).

In growth on dicarboxylic acids or acetate, formation of PEP and intermediates of the glycolytic pathway requires decarboxylation either of oxalacetate by PEP carboxykinase (pck), giving PEP in an ATP-dependent reaction, or of malate by the malic enzymes (mez) giving pyruvate, and hence PEP via PEP synthase (pps). Deficiency of both routes is required for substantial impairment of growth on succinate, i.e., pck mez (108) or pck pps (98), and would be expected to confer a requirement for, e.g., glycerol. PEP synthase is required also for growth on lactate or pyruvate (55, 190).

The several reactions are subject to a variety of metabolic effectors, e.g., PEP carboxylase, activation by acetyl coenzyme A and fructose-1,6-P₂ and inhibition by aspartate (151); PEP carboxykinase, inhibition by nucleotides and by PEP (99, 136); NAD-malic enzyme, activation by aspartate and inhibition by coenzyme A (216); and PEP synthase, inhibition by PEP and oxalacetate (44). Expression is also differentially regulated, growth on glucose giving highest expression for ppc and lowest for pck (100, 198), pps (44, 107), and the malic enzymes (108, 153). It is a formidable challenge to clarify the normal roles of the several parallel and opposing reactions. Approaches have included enzymes studied in pairs (44), evaluation of activity by using in vivo concentrations of ligands (151), and analysis of mutants altered in effector sensitivity (196). A recent line has been the quantitative evaluation of effects on growth rate, yield, and oxygen use in strains with controlled increases in enzyme levels (40, 41, 42).

METABOLISM VIA 6-PHOSPHOGLUCONATE

Oxidative Branch of the Pentose-P Pathway

pgi zwf mutants do not grow on glucose and are blocked in productive glucose metabolism (80, 81). pgi gnd double mutants, likewise, do not grow on glucose (138). pgi pgl double mutants have a leaky glucose-negative phenotype (138), fitting with a lactonase reaction that also proceeds nonenzymatically. Mutants in any single one of the three reactions grow at near normal rates on glucose in batch culture (89). Analogously, growth on gluconate, which mainly uses the Entner-Doudoroff pathway (see below), is completely blocked in edd gnd double mutants (80) but relatively normal in gnd single mutants (89). However, it should be noted that "normal" in physiology and metabolism depends on the sensitivity of measurement. In mixed cultures with the wild type in glucose-limited chemostats, a gnd mutant was rapidly counterselected (110) while a zwf mutant was almost stable (70).

The gnd gene has been subject to the most detailed study of any in this chapter, e.g., specialized transducing phages (212), cell-free enzyme synthesis (123), and comparisons of sequence, expression, and fitness (19, 127, 150). Expression (enzyme activity or protein) is proportional to growth rate (76, 214), and the threefold difference for cells in minimal medium with acetate or glucose correlates with the increased amount of gnd mRNA rather than with changes in its physical or functional half life (163). The growth rate effect was not seen in gnd-lac operon fusions (14) but was seen in gnd-lac protein fusions unless they were early in the gene (15), where a negatively acting antisense Shine-Dalgarno sequence has been analyzed (38).

The modest growth rate regulation of zwf expression is also correlated with mRNA (177). cis-acting mutations increasing zwf expression (88) are new promoters considerably upstream from the gene (177). zwf expression is increased severalfold by superoxide-generating agents such as paraquat and belongs to the soxR and mar regulons (103).

Nonoxidative Branch of the Pentose-P Pathway

Any one of the three (D) pentose-P’s may be the initial metabolite: ribulose-5-P from the gnd reaction, ribose-5-P from ribose, or xylulose-5-P from xylose and l-arabinose, and both ribose-P epimerase (rpe) and ribose-P isomerase (rpi) are needed to make the other substrate for the transketolase reaction. Two ribose-P isomerase activities, A and B, were reported in E. coli (65, 74, 188). rpiA mutants lack activity A and are ribose auxotrophs, but contain sufficient activity B for growth on ribose (188; K. I. Sorensen and B. Hove-Jensen, submitted for publication). rpiB mutants are impaired on ribose but are not ribose auxotrophs (Sorensen and Hove-Jensen, submitted). Overexpression of activity B (rpiR) suppresses the ribose requirement of rpiA mutants (74; Sorensen and Hove-Jensen, submitted).

As usually written, transformation of pentose-P’s into fructose-6-P and glyceraldehyde-3-P involves the sequential action of transketolase, transaldolase, and transketolase again, 3 pentose-P’s giving 2.5 hexose-P’s. Transketolase (tktA) mutants are aromatic auxotrophs also impaired on pentoses (128, 129) and deficient in heptose (72). Transketolase B (tktB), present at lower activity, suppresses tktA when overexpressed (119). The tktA tktB double mutant has also been described (218). Transaldolase mutants have not yet been reported; however, see Sprenger et al. (194b).

Functions of the Pentose-P Pathway

Pentose synthesis may occur by both the oxidative and nonoxidative branches of the pentose-P pathway, as shown by labeling experiments (36, 126, 129, 131) and the fact that a block in both branches (rpiA excepted) is needed for pentose auxotrophy (129). Such experiments also show that the oxidative branch is impaired anaerobically.

A second function may be to provide NADPH for biosynthesis. Experiments with labeling and mutants, however, showed that it need not be the main source (56).

A third function would be as a long route between glucose-6-P and fructose-6-P, i.e., the hexose monophosphate shunt, as in growth on glucose of a pgi mutant at ca. one-third normal rate. Flux in the wild type is probably of the same magnitude. In the latter case, fructose-6-P and glucose-6-P may equilibrate (131), so that the pathway would effectively be a cycle for complete oxidation of hexose monophosphate to CO₂. However, such a route cannot readily function exclusively, since mutants blocked at phosphofructokinase do not grow on glucose or arabinose (61).

Fourth, the nonoxidative branch of the pentose-P pathway is also needed for growth on pentoses and for the portion of gluconate metabolism not using the Entner-Doudoroff pathway (159).

Gluconate Metabolism

In many oxidative bacteria, sugar metabolism occurs primarily via 6-phosphogluconate and its cleavage by the two Entner-Doudoroff enzymes, 6-phosphogluconate dehydrase (edd) and 2-keto-3-deoxy-6-phosphogluconate aldolase (eda), giving pyruvate and glyceraldehyde-3-P. The pathway comes in various forms (49). Enteric bacteria typically use it for the inducible metabolism of gluconate (1-position oxidized glucose), which is converted to 6-phosphogluconate by gluconokinase (73, 84, 86, 122). The aldolase is also involved in catabolism of glucuronate and galacturonate and possibly glyoxylate (162). edd mutants grow at a reduced rate on gluconate, using the pentose-P pathway (217). eda mutants (75, 78, 166) do not grow on the uronic acids (or on gluconate—but that may be related to the toxicity of intermediate accumulation, since edd eda double mutants do grow on gluconate).

eda is immediately downstream in an operon from edd, with the major gluconate-induced transcript (71, 77) probably governed by gntR (12, 220), which is also involved in expression of gluconate transport and gluconokinase (122). A separate transcript for eda (71, 77) may respond to kdgR, which also governs other elements of 2-keto-3-deoxygluconate metabolism (165).

Although under the usual laboratory conditions the metabolism of glucose itself in E. coli does not occur via the Entner-Doudoroff pathway, a glucose dehydrogenase (gcd) apoenzyme which requires the cofactor pyrroloquinoline quinone is widely present (30). Pyrroloquinoline quinone addition, or mutation allowing its synthesis (25), permits metabolism of glucose via gluconate (77) in mutants otherwise blocked (2, 115), and formation of gluconate in wild type (116). Oxidation in the periplasm is coupled to ubiquinone reduction and is energy conserving (145, 205).

PROBLEMS

Gene Expression

With the obvious exceptions of the inducible Entner-Doudoroff pathway and certain reactions beyond pyruvate, many of the enzymes are constitutively expressed, their levels not being sharply dependent on apparent metabolic need, as shown for 6-phosphogluconate dehydrogenase: the difference in enzyme level between a situation in which it is probably not used (anaerobic growth) and one in which it is used (aerobic growth on gluconate) is not more than twofold (76, 200); and in growth of an edd mutant on gluconate, in which higher expression of gnd would increase the growth rate (149) and in which gluconate 6-P levels are high (159), the dehydrogenase level was the same as in the wild type (76). Likewise, in a zwf mutant, which had no detectable gluconate-6-P in growth on glucose (159), the dehydrogenase levels were the same in growth on glucose and gluconate (80). Similar arguments against substrate-dependent expression can be made for some of the other genes (but see below).

A second consideration is that by contrast with highly inducible enzymes, specific regulatory genes are not known. The lack of specific positive factors for their expression also fits with the relative ease of obtaining efficient cell-free synthesis (gnd [122] and pfkA [201]). There are no operons, because the various genes are unlinked; pgk-fbaA may prove an exception. Also, the fact that cloning on multicopy plasmids gives high enzyme levels argues against titratable elements necessary for expression (76) or autogenous control.

However, for most of the genes, systematic studies are rare. Furthermore, there is substantial evidence for global regulation of expression, e.g., growth rate control of gnd and soxR control of zwf, and such knowledge is rapidly growing. Most of the genes are probably not subject to conventional glucose repression, with high enzyme levels found on glucose or on glycerol. There have been many observations of certain glycolytic enzymes being present at higher levels in anaerobic than aerobic culture (e.g., glucose-limited chemostats [170, 200] and batch culture [135, 189]). In general, such differences are less than threefold in the steady state, but they may be much larger after shifts between different conditions (67, 189).

Metabolism

Metabolic studies are scarce (82). One type of work involves describing fluxes and metabolite concentrations: there is a major source of data on general metabolic flow in wild-type E. coli (172) and several on metabolite levels in a variety of situations (see, e.g., references 141 and 152). Analysis can be complicated, especially when two pathways function simultaneously (e.g., Embden-Meyerhof and pentose-P) and when actual rates (forward and reverse) for reversible reactions and pathways are sought (see, e.g., references 9 and 131).

The other type of work involves relating fluxes to in vitro characteristics of the enzymes, i.e., the modeling of metabolism and determination of what controls what. This is a subject in which theory is much in advance of practice and studies of microorganisms, let alone E. coli, lag considerably. Early studies emphasized irreversible allosteric reactions sensitive to effectors (e.g., phosphofructokinase and pyruvate kinase) (109, 141). Glucose flux in a range of steady-state situations could be fitted by an equation with only glucose-6-P as inhibitor and fructose-1,6-P₂ as activator, their targets unknown (66). Modeling studies involving the in vivo metabolite concentrations with the enzyme in vitro are limited (159, 160, 169) and modeling to the kinetic equations is even more limited (9, 141).

One newer approach is to vary the amount of a single enzyme of interest (9, 40, 41, 42). Another is the use of mutants altered in allostery. There are cases of deleterious effects, such as Pfk-2* impairing gluconeogenesis (60), and high levels of AMP-insensitive fructose-1,6-bisphosphatase impairing glycolysis (183). However, of equal interest are examples showing the relative tolerance of cells to such differences (39, 62, 173, 183).

Finally, three interesting complications in metabolism and function should be mentioned. First is the possibility that pathways are organized as complexes with channeling of metabolites from enzyme to enzyme; there has been consideration of E. coli glycolysis in this regard (see, e.g., reference 102). Second is ignorance about isozyme function. Third is the problem of toxicities, in which, as cited for some of the mutants, growth on permissive substances is prevented by the substrate of the blocked pathway, so that impairment of even a secondary pathway may prevent growth. Inhibition is sometimes accompanied by substantial accumulation of metabolites before the block, but accumulation of a metabolite is not always toxic (e.g., reference 81), and there is no general explanation. Aside from the possible specific direct effects of high levels of normal metabolites (81, 174), methylglyoxal formation (see above), catabolite repression, and osmotically remedied effects (121) have all been implicated. The cases of glyoxalase and 6-phosphogluconolactonase show the importance of enzymes in reducing substrate concentrations.

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