Substrate inhibition lactate

ISOTOPE EXCHANGE AT EQUILIBRIUM ISOTOPE TRAPPING LACTATE DEHYDROGENASE LIGAND EXCLUSION MODEL NONPRODUCTIVE COMPLEXES PRODUCT INHIBITION SUBSTRATE INHIBITION... 

ISOTOPE TRAPPING STICKY SUBSTRATES Substrate-induced conformational change, INDUCED FIT MODEL SUBSTRATE INHIBITION ABORTIVE COMPLEX FORMATION LACTATE DEHYDROGENASE LEE-WILSON EQUATION... 

K. M. Moreton, and J. J. Holbrook, Removal of substrate inhibition in a lactate dehydrogenase from human muscle by a single residue, FEBS Lett. 1996, 399, 193-197. 

De Bruijne, A.W., Vreeburg, H., and Van Steveninck, J. (1985) Alternative-substrate inhibition of L-lactate transport via the monocarboxylate-specific carrier system in human erythrocytes. Biochimica et Biophysica Acta, 812, 841-844. 

Figure 6-1. The steps of glycolysis. Feedback inhibition of glucose phosphorylation by hexokinase, inhibition of pyruvate kinase, and the main regulatory, rate-limiting step catalyzed by phosphofructoki-nase (PFK-I) are indicated, pyruvate formation and substrate-level phosphorylation are the main outcomes of these reactions. Regeneration of NAD occurs by reduction of pyruvate to lactate during anaerobic glycolysis.

Feeding of fresh medium prevents the limitation of growth from a lack of substrates as well as inhibition from the accumulation of metabolic by-products. This has recently been investigated in detail for lactate, when Patel et al. found that a lactate concentration of more than 20 mM inhibits cell proliferation and metabolism, although it has little effect on cell differentiation [51]. 

Mechanism and susceptibility factors Biguanides in high doses inhibit the oxidation of carbohydrate substrates by affecting mitochondrial function. Anoxidative carbohydrate metabolism stimulates the production of lactate. High lactate production leads to lactic acidosis (type B) with a low pH (<6.95). Hyperlactatemia was common in patients taking buformin, even without alcoholism or impaired liver, kidney, or cardiac function (70). 

Similar to what has been shown in Table 8.1 for specific growth rate, many mathematical expressions listed in Table 8.3 employ Monod-type structures for limiting phenomena, and Aiba and Shoda-type structures for inhibitory behavior. Limiting components for cell death are lactate and ammonia, that is, the presence of these byproducts increases the specific cell death rate. On the other hand, substrates, such as glucose and glutamine, inhibit cell death (Equations 48 to 52). 

Phosphatidylcholine is preferentially synthesized in lactating mammary tissue (Kinsella, 1973), possibly regulated by the differential activities of choline kinase and ethanolamine kinase. Choline kinase has a lower Km and a higher Vmax with its substrate than does ethanolamine kinase. Also, choline kinase is inhibited slightly by ethanolamine, whereas choline is a potent competitive inhibitor of ethanolamine kinase. Thus, the intracellular concentration of choline probably regulates the synthesis of these two phos-phoglycerides (Infante and Kinsella, 1976). 

The role of L-lactate dehydrogenase in the physiology of aerobic yeast is not clear. It has been shown that its presence in yeast depends on the availability of oxygen (306), and that in the presence of antimycin A, which inhibits electron transfer to cytochrome c from NADH-linked substrates, L-or D-lactate can partially support the growth of Saccharo-myces cerevisiae (307). Under these conditions, cyanide inhibited the growth. Therefore, it has been concluded that l- and D-lactate-cyto-chrome c reductases can feed electrons to the respiratory chain at the level of cytochrome c and provide energy through the third site of oxidative phosphorylation (307). 

D-Lactate cytochrome c reductase is inhibited by p-mercuriphenyl sulfonate salts, metal chelators, and dicarboxylic acids such as oxalate and oxaloacetate (Table XVI) (312, 314, 315). According to Nygaard (314), salts (cations) inhibit at the acceptor site, and dicarboxylic acids at the substrate site. Cremona and Singer (315) have studied the inhibitions by metal chelators and by oxalate. They recognized two types of inhibition. One type of inhibition is that which is caused by EDTA or oxalate. This kind of inhibition is reversed immediately upon dilution of the enzyme-inhibitor mixture. The second is that which results from addition of o-phenanthroline. Enzyme preparations treated with o-phenanthroline bind 2 moles of the chelator per mole of Zn . This complex is stable and inactive, and does not result in the release of Zri . The inactive... 

As well as alternative substrates, there have been a number of studies on inhibitors of flavocytochrome 62- Known inhibitors include D-lactate (16, 92-95), pyruvate (16, 58, 60, 96), propionate (96), DL-man-delate (90, 91), sulfite (60), and oxalate (16, 60, 97). Values of K, for these inhibitors and the conditions and types of enzyme used can be found in the papers referenced above. All of the above inhibitors show typical competitive inhibition except pyruvate and oxalate, for which mixed inhibition has been observed (60, 97). Inhibition has also been reported for excess substrate with the intact enzymes from both S. cerevisiae (16) and H. anomala (92), though not apparently with the cleaved enzyme from S. cerevisiae (16). It is possible that inhibition by excess substrate arises either from different binding modes at the active site or from a second lower affinity binding site elsewhere on the enzyme. 

A second mechanism of protection from caries is the incorporation of fluoride into bacterial biofilms where it inhibits enolase. Enolase catalyzes the production of phospho-enolpyruvate, the precursor of lactate in glycolysis, from 2-phosphoglycerate during glycolysis (Fig. 16.7 - see also Fig. 1.7). In addition, oral bacterial uptake of mono- and disaccharides mostly utilizes the phosphoenolpyruvate transport system to transfer them into the cytosol (Sect. 15.2.2). Fluoride therefore inhibits not only lactic acid production, but also the phosphoenolpyruvate transport system-mediated uptake of saccharide substrates. In short, fluoride inhibits saccharolytic fermentation by many oral bacteria. 

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