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PubMed1992

Decrease of pyruvate dehydrogenase phosphatase activity in patients with congenital lactic acidemia.

We developed an assay method for pyruvate dehydrogenase phosphatase activity using [1-14C]pyruvate and measured pyruvate dehydrogenase phosphatase activity in cultured skin fibroblasts from three patients with congenital lactic acidemia due to a defect in activation of the pyruvate dehydrogenase complex. The enzyme activity of their fibroblasts was significantly reduced to 50.7%, 64.6% and 63.1% of that of control fibroblasts. These observations suggest that the defect in activation of the pyruvate dehydrogenase complex in these patients might be due to a reduction in pyruvate dehydrogenase phosphatase activity.

Acidosis, Lactic↗
PubMed1982

Diacetyl: a new substrate in the overall reaction of the pyruvate dehydrogenase complex.

Pig heart pyruvate dehydrogenase complex (pyruvate: lipoamide oxidoreductase (decarboxylating and acceptor-acetylating), EC 1.2.4.1) catalyzes the decomposition of diacetyl to acetate, acetyl-CoA and produces reduced NAD+ with 1:1:1 stoichiometry. The reaction rate with diacetyl is approximately 7.1% of that with pyruvate. The Km value for diacetyl was found to be 0.46 mM. Acetoin and acetaldehyde inhibit the pyruvate dehydrogenase-catalyzed reaction of diacetyl with Ki values of 0.91 mM and 0.48 mM, respectively. Inhibition patterns show that they are competitive inhibitors versus diacetyl. Acetate, as product, does not inhibit the enzymatic decomposition of diacetyl. Diacetyl is not only an alternative substrate in the pyruvate dehydrogenase reaction, but a competitive inhibitor versus pyruvate with a Ki value of 0.43 mM.

Acetaldehyde↗
PubMed1982

Ammonium ions enhance the flow through the pyruvate dehydrogenase in Ehrlich ascites tumor cells.

The flow through pyruvate dehydrogenase was assayed in glycolysing cells by the evolution of 14CO2 from [1-14C] pyruvate. Parallel incubations were carried out in high bicarbonate buffer (25 mM) and in bicarbonate-free buffer. The activation of the complex by NH+4 was only observed in high bicarbonate buffer, because the dilution of labelled CO2 in the presence of an excess of bicarbonate enables the quantitative determination of labelled CO2 evolved from pyruvate in the decarboxylase step. In the bicarbonate-free buffer the activation of the complex was not observed, because the 14CO2 evolved from pyruvate was consumed by biosynthetic processes inside the cell. On the contrary in isolated hepatocytes the NH+4 activation of the pyruvate dehydrogenase was observed in both buffers. In Ehrlich ascites cells, in common with other mammalian tissues, pyruvate dehydrogenase activity was found to be inversely correlated to the intramitochondrial ATP/ADP ratio.

Adenine Nucleotides↗
PubMed1994

Pyruvate ferredoxin oxidoreductases of the hyperthermophilic archaeon, Pyrococcus furiosus, and the hyperthermophilic bacterium, Thermotoga maritima, have different catalytic mechanisms.

Pyruvate ferredoxin oxidoreductase (POR) has been previously purified from two hyperthermophiles, the archaeon Pyrococcus furiosus (Pf, Topt = 100 degrees C) and the bacterium Thermotoga maritima (Tm, Topt = 80 degrees C). Each catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA and CO2 near the optimal growth temperature of the organism and are virtually inactive at 25 degrees C. Both PORs contain a thiamine pyrophosphate (TPP) cofactor and at least two [4Fe-4S] ferredoxin-type clusters. We have now shown, using EPR spectroscopy and metal analyses, that PfPOR also contains an unusual copper center that is not present in Tm POR. In addition, distinct catalytic intermediates were generated in both enzymes by the addition, separately and in combination, of the substrates pyruvate and CoASH, and these were examined by EPR spectroscopy. The addition of pyruvate to oxidized Pf POR produced an isotropic signal centered at g = 2.01, which was measurably broader in the presence of pyruvate-2(13)C. This signal, which was assigned to a (hydroxyethyl)thiamine pyrophosphate radical intermediate, was not observed in Tm POR under the same experimental conditions. Incubation of the oxidized enzymes with CoASH resulted in the partial reduction of the copper site in Pf POR and the partial reduction of a novel iron-sulfur center in Tm POR, which was not seen in the dithionite-reduced enzyme. The addition of both pyruvate and CoASH to the PORs in their oxidized states resulted in the reduction of the same iron-sulfur centers that are reduced by sodium dithionite.(ABSTRACT TRUNCATED AT 250 WORDS)

Archaea↗
PubMed1984

Bromopyruvate as an active-site-directed inhibitor of the pyruvate dehydrogenase multienzyme complex from Escherichia coli.

Bromopyruvate behaves as an active-site-directed inhibitor of the pyruvate decarboxylase (E1) component of the pyruvate dehydrogenase complex of Escherichia coli. It requires the cofactor thiamin pyrophosphate (TPP) and acts initially as an inhibitor competitive with pyruvate (Ki ca. 90 microM) but then proceeds to react irreversibly with the enzyme, probably with the thiol group of a cysteine residue. E1 catalyzes the decomposition of bromopyruvate, the enzyme becoming inactivated once every 40-60 turnovers. Bromopyruvate also inactivates the intact pyruvate dehydrogenase complex in a TPP-dependent process, but the inhibition is more rapid and is mechanistically different. Under these conditions, bromopyruvate is decarboxylated, and the lipoic acid residues in the lipoate acetyltransferase (E2) component become reductively bromoacetylated. Further bromopyruvate then reacts with the new thiol groups thus generated in the lipoic acid residues, inactivating the complex. If reaction with the lipoic acid residues is prevented by prior treatment of the complex with N-ethylmaleimide in the presence of pyruvate, the mode of inhibition reverts to irreversible reaction with the E1 component. In both types of inhibition of E1, reaction of 1 mol of bromopyruvate/mol of E1 chain is required for complete inactivation, and all the evidence is consistent with reaction taking place at or near the pyruvate binding site.

Affinity Labels↗
PubMed1997

2-Oxo-3-alkynoic acids, universal mechanism-based inactivators of thiamin diphosphate-dependent decarboxylases: synthesis and evidence for potent inactivation of the pyruvate dehydrogenase multienzyme complex.

A new class of compounds, the 2-oxo-3-alkynoic acids with a phenyl substituent at carbon 4 was reported by the authors as potent irreversible and mechanism-based inhibitors of the thiamin diphosphate- (ThDP-) dependent enzyme pyruvate decarboxylase [Chiu, C.-F., & Jordan, F. (1994) J. Org. Chem. 59, 5763-5766]. The method has been successfully extended to the synthesis of the 4-, 5-, and 7-carbon aliphatic members of this family of compounds. These three compounds were then tested on three ThDP-dependent pyruvate decarboxylases: the Escherichia coli pyruvate dehydrogenase multienzyme complex (PDHc) and its E1 (ThDP-dependent) component, pyruvate oxidase (POX, phosphorylating; from Lactobacillus plantarum),and pyruvate decarboxylase (PDC) from Saccharomycescerevisiae. All three enzymes were irreversibly inhibited by the new compounds. The 4-carbon acid is the best substrate-analog inactivator known to date for PDHc, more potent than either fluoropyruvate or bromopyruvate. The following conclusions were drawn from extensive studies with PDHc: (a) The kinetics of inactivation of PDH complexes and of resolved E1 by 2-oxo-3-alkynoic acids is time- and concentration-dependent. (b) The 4-carbon acid has a Ki 2 orders of magnitude stronger than the 5-carbon acid, clearly demonstrating the substrate specificity of PDHc. (c) The rate of inactivation of PDH complexes and of resolved E1 by 2-oxo-3-alkynoic acids is enhanced by the addition of ThDP and MgCl2. (d) Pyruvate completely protects E1 and partially protects PDHc from inactivation by 2-oxo-3-butynoic acid. (e) E1 but not E2-E3 is the target of inactivation by 2-oxo-3-butynoic acid. (f) Inactivation of E1 by 2-oxo-3-butynoic acid is accompanied by modification of 1.3 cysteines/E1 monomer. The order of reactivity with the 4-carbon acid was PDHc > POX > PDC. While the order of reactivity with PDHc and POX was 2-oxo-3-butynoic acid > 2-oxo-3-pentynoic acid > 2-oxo-3-heptynoic acid, the order of reactivity was reversed with PDC.

Bacterial Proteins↗
PubMed1983

Mechanism of activation of pyruvate dehydrogenase by mitogens in pig lymphocytes.

The activity of pyruvate dehydrogenase in extracts of pig mesenteric lymphocytes was measured under different preincubation conditions. The mitogens concanavalin A and ionophore A23187 both increased pyruvate dehydrogenase activity. In both cases activation required extracellular Ca2+. Digitonin-permeabilized cells required 0.5 microM free Ca2+ for half-maximal activation of pyruvate dehydrogenase. The stimulation by concanavalin A in intact cells was probably not due to changes in effectors of pyruvate dehydrogenase kinase. This evidence suggests that activation of pyruvate dehydrogenase is by Ca2+ activation of pyruvate dehydrogenase phosphatase and supports the view that the cytoplasmic free [Ca2+] rises to something less than 1 microM on stimulation with mitogens.

Animals↗
PubMed2000

Marked differences between two isoforms of human pyruvate dehydrogenase kinase.

Pyruvate dehydrogenase kinase (PDK) isoforms 2 and 3 were produced via co-expression with the chaperonins GroEL and GroES and purified with high specific activities in affinity tag-free forms. By using human components, we have evaluated how binding to the lipoyl domains of the dihydrolipoyl acetyltransferase (E2) produces the predominant changes in the rates of phosphorylation of the pyruvate dehydrogenase (E1) component by PDK2 and PDK3. E2 assembles as a 60-mer via its C-terminal domain and has mobile connections to an E1-binding domain and then two lipoyl domains, L2 and L1 at the N terminus. PDK3 was activated 17-fold by E2; the majority of this activation was facilitated by the free L2 domain (half-maximal activation at 3.3 microm L2). The direct activation of PDK3 by the L2 domain resulted in a 12.8-fold increase in k(cat) along with about a 2-fold decrease in the K(m) of PDK3 for E1. PDK3 was poorly inhibited by pyruvate or dichloroacetate (DCA). PDK3 activity was stimulated upon reductive acetylation of L1 and L2 when full activation of PDK3 by E2 was avoided (e.g. using free lipoyl domains or ADP-inhibited E2-activated PDK3). In marked contrast, PDK2 was not responsive to free lipoyl domains, but the E2-60-mer enhanced PDK2 activity by 10-fold. E2 activation of PDK2 resulted in a greatly enhanced sensitivity to inhibition by pyruvate or DCA; pyruvate was effective at significantly lower levels than DCA. E2-activated PDK2 activity was stimulated >/=3-fold by reductive acetylation of E2; stimulated PDK2 retained high sensitivity to inhibition by ADP and DCA. Thus, PDK3 is directly activated by the L2 domain, and fully activated PDK3 is relatively insensitive to feed-forward (pyruvate) and feed-back (acetylating) effectors. PDK2 was activated only by assembled E2, and this activated state beget high responsiveness to those effectors.

Acetyl Coenzyme A↗
PubMed1964

PYRUVATE FERMENTATION BY STREPTOCOCCUS FAECALIS.

Deibel, R. H. (American Meat Institute Foundation, Chicago, Ill.), and C. F. Niven, Jr. Pyruvate fermentation by Streptococcus faecalis. J. Bacteriol. 88:4-10. 1964.-Streptococcus faecalis, as opposed to S. faecium, utilizes pyruvate as an energy source for growth. The fermentation is adaptive, as demonstrated by growth experiments in a casein-hydrolysate medium and the fermentation of pyruvate by cell suspensions. The principal products of pyruvate catabolism were acetoin, CO(2), and lactic, acetic, and formic acids, although carbon recoveries were low due to the formation of slime. End-product analyses suggested that both the phosphoroclastic and dismutation systems were active in pyruvate breakdown. Studies with cell-free extracts indicated a thiamine diphosphate requirement for active pyruvate catabolism. The involvement of lipoic acid in the phosphoroclastic system was investigated, and, although inconclusive results were obtained, no association of this cofactor with phosphoroclastic activity could be made.

Acetates↗
PubMed1965

PYRUVATE METABOLISM, CARBON DIOXIDE ASSIMILATION, AND NITROGEN FIXATION BY AN ACHROMOBACTER SPECIES.

Hamilton, I. R. (University of Wisconsin, Madison), R. H. Burris, P. W. Wilson, and C. H. Wang. Pyruvate metabolism and carbon dioxide assimilation by an Achromobacter species. J. Bacteriol. 89:647-653. 1965.-Carbon dioxide fixation by washed whole cells of Achromobacter N4-B has been observed during anaerobic pyruvate metabolism with both nitrogen- and NH(4) (+)-grown cells. Labeled sodium bicarbonate-C(14) was assimilated into cells by a mechanism requiring pyruvate under conditions of nitrogen fixation, nitrogenase induction, and assimilation of NH(4) (+). Of the assimilated radioactivity, 89% appeared in six amino acids and two ninhydrin-positive unknown compounds, with the distribution of the label essentially independent of the nitrogen nutritional state of the organism. Aspartic and glutamic acids were the most highly labeled, with lesser amounts in glycine, alanine, ornithine, arginine, and the unknowns. All of the radioactivity extracted from these cells by ethanol-boiling water appeared in a protein fraction precipitated by 20% trichloroacetic acid. Radiorespirometric experiments with individually labeled pyruvate substrates demonstrated the preferential decarboxylation of the C-1 of pyruvate by this organism in a flowing helium gas phase. This decarboxylation was almost completely inhibited by using flowing nitrogen in place of helium; the addition of 0.5% CO(2) to the flowing nitrogen prevented inhibition and allowed 70% of the expected CO(2) evolution. These results, coupled with those from growth experiments, indicate a carbon dioxide requirement for anaerobic growth and pyruvate metabolism, which appears to be coupled to the formation of protein precursors.

Achromobacter↗
PubMed1984

Parallel stimulation by Ca2+ of inotropism and pyruvate dehydrogenase in perfused heart.

The effects of extracellular Ca2+ (0.375-3.75 mM) on pyruvate oxidation and active form of the pyruvate dehydrogenase complex (PDCa) were quantitated in perfused guinea pig hearts in relation to inotropism, hydraulic work performance, and myocardial oxygen uptake (MVO2). The effects of afterload and norepinephrine (NE), alone or combined with the Ca2+ channel blocker D 600, were also examined. Hearts utilized 1-5 mM pyruvate in presence of 5 mM DL-3-hydroxybutyrate as substrates. Pyruvate oxidation and MVO2 increased essentially in parallel regardless of whether inotropism and energy metabolism were stimulated by increasing the Ca2+ concentration [( Ca2+]), the NE concentration [( NE]), or the afterload. PDCa activity was also directly related to [Ca2+], [NE], and afterload, respectively. Elevated [Ca2+] failed, however, to stimulate pyruvate oxidation and PDCa activity when MVO2 was held constant by an appropriate decrease in afterload at constant preload. Compound D 600, theophylline, and dibutyryl adenosine 3',5'-cyclic monophosphate also produced parallel alterations in cardiac mechanics, pyruvate oxidation, and MVO2. The striking proportionality between PDCa parameters, MVO2, and cardiac mechanics during the various alterations in cellular Ca2+ metabolism seemed to suggest that the observed Ca2+ stimulation of the PDC might be mainly secondary to increased myocardial energy utilization and myocyte respiration. Evidence for an additional direct effect of Ca2+ on the intact PDC system was not obtained.

Animals↗
PubMed2004

Enhanced rat beta-cell proliferation in 60% pancreatectomized islets by increased glucose metabolic flux through pyruvate carboxylase pathway.

Islet beta-cell proliferation is a very important component of beta-cell adaptation to insulin resistance and prevention of type 2 diabetes mellitus. However, we know little about the mechanisms of beta-cell proliferation. We now investigate the relationship between pyruvate carboxylase (PC) pathway activity and islet cell proliferation 5 days after 60% pancreatectomy (Px). Islet cell number, protein, and DNA content, indicators of beta-cell proliferation, were increased two- to threefold 5 days after Px. PC and pyruvate dehydrogenase (PDH) activities increased only approximately 1.3-fold; however, islet pyruvate content and malate release from isolated islet mitochondria were approximately threefold increased in Px islets. The latter is an indicator of pyruvate-malate cycle activity, indicating that most of the increased pyruvate was converted to oxaloacetate (OAA) through the PC pathway. The contents of OAA and malate, intermediates of the pyruvate-malate cycle, were also increased threefold. PDH and citrate content were only slightly increased. Importantly, the changes in cell proliferation parameters, glucose utilization, and oxidation and malate release were partially blocked by in vivo treatment with the PC inhibitor phenylacetic acid. Our results suggest that enhanced PC pathway in Px islets may have an important role in islet cell proliferation.

Animals↗
PubMed1979

Pyruvate carboxylase deficiency and lactic acidosis in a retarded child without Leigh's disease.

A child with lactic acidosis, severe mental and developmental retardation, and proximal renal tubular acidosis is presented. Biopsy and autopsy studies show severe hepatic, renal cortical, and cerebral deficiencies in pyruvate carboxylase (EC 6.4.1.1) activity. The patient had 1.81 +/- 0.20 units/g fresh weight at biopsy and 0.75 +/- 0.07 units/g fresh weight hepatic pyruvate carboxylase activity at autopsy compared with 10.9, 11.3, and 9.5 units/g fresh weight in two autopsy and one biopsy controls, respectively. The patient's renal cortical pyruvate carboxylase activity at autopsy was 0.008 +/- 0.004 units/g fresh weight compared with 5.05 units/g in the autopsy control. The patient had no detectable (less than 0.018 units/g fresh weight) cerebral pyruvate carboxylase activity at autopsy compared with 0.44, 0.53, and 0.695 units/g in the autopsy cerebrum of one human and two rhesus monkeys, respectively. Pyruvate dehydrogenase complex, phosphoenolpyruvate carboxykinase (PEPCK, EC 4.1.1.32), and fructose-1,6-bisphosphatase (EC 3.1.3.11) activities were in the normal range. The patient's urine pH was above 7.9 when the total serum CO2 was greater than 7.8 mM. However, the patient was able to acidify the urine to pH 5.1 when the total serum CO2 was 1.6 mM. The neuropathologic examination of the brain at autopsy revealed no sign of Leigh's disease, although developmental and degenerative lesions were observed. This is the first reported patient with a primary deficiency in hepatic, renal, and cerebral pyruvate carboxylase deficiency in whom the neuropathologic lesions, distinct from those of Leigh's disease, and proximal renal tubular acidosis have both been documented.

Acidosis↗
PubMed1998

Kinetic, dynamic, and pathway studies of glycerol metabolism by Klebsiella pneumoniae in anaerobic continuous culture: IV. Enzymes and fluxes of pyruvate metabolism.

The activities of pyruvate kinase (PK), pyruvate: formate-lyase (PFL), pyruvate dehydrogenase (PDH), and citrate synthase (CS) involved in the anaerobic glycerol conversion by Klebsiella pneumoniae were studied in continuous culture under conditions of steady states and sustained oscillations. Both the in vitro and in vivo activities of PK, PFL, and PDH are strongly affected by the substrate concentration and its uptake rate, as is the in vitro activity of CS. The flux from phosphoenolpyruvate to pyruvate is found to be mainly regulated on a genetic level by the synthesis rate of PK, particularly at low substrate concentration and low growth rate. In contrast, the conversion of pyruvate to acetyl-CoA is mainly regulated on a metabolic level by the in vivo activities of PFL and PDH. The ratio of in vitro to in vivo activities is in the range of 1 to 1.5 for PK, 5 to 17 for PFL and 5 to 80 for PDH under the experimental conditions. The regulation of in vivo activity and synthesis of these enzymes is sensitive to fluctuations of culture conditions, leading to oscillations of both the in vitro and in vivo activities. In particular, PFL is strongly affected during oscillations; its average in vitro activity is only about half of its corresponding steady-state value under similar environmental conditions. The average in vitro activities of PDH and PK under oscillations are close to their corresponding steady-state values. In contrast to all other enzymes measured for the glycerol metabolism by K. pneumoniae PFL and PDH are more effectively in vivo utilized under oscillations than under steady state, underlining the peculiar role of pyruvate metabolism in the dynamic responses of the culture.

Acetyltransferases↗
PubMed2002

Defects of pyruvate metabolism and the Krebs cycle.

Seizures and metabolic disease are frequently associated, either indirectly as a consequence of the metabolically caused brain dysgenesis or directly by the metabolic derangement. This article describes defects in pyruvate metabolism (pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency) and Krebs cycle defects such as fumarase deficiency. Clinical characterizations and diagnostic strategies have been developed for each of these diseases. In contrast, very little is known about the specific epileptic features in these disorders. In females with a pyruvate dehydrogenase deficiency E1alpha owing to the mutation in the subunit E1alpha of the pyruvate dehydrogenase complex West's syndrome associated with large ventricles and corpus callosum agenesis on magnetic resonance imaging can be the main feature of the disease. In fumarase deficiency, prenatal brain dysgenesis is the most prominent feature of the disease. Diagnosis of these disorders requires measurements of lactate and pyruvate in plasma and cerebrospinal fluid, analysis of amino acids in plasma and organic acids in urine, and neuroradiologic investigations. Further biochemical and molecular analysis leads to a definitive diagnosis and opens the way to adequate treatment, genetic counseling, and prenatal diagnosis.

Brain↗
PubMedDate not supplied

[Pyruvate decarboxylase inactivation by interaction with substrate and molecular oxygen].

Pyruvate may promote the yeast pyruvate decarboxylase inactivation when affected by molecular oxygen. In the presence of pyruvate and O2 inactivation of enzyme increases with the initial substrate concentration increasing. pH-dependence of pyruvate decarboxylase inactivation under joint action of substrate and O2 has maximum in the region 6.9-7.5. It is suggested that the influence of pyruvate and molecular oxygen is connected with the coenzyme-substrate complex oxidation in an active site of yeast pyruvate decarboxylase on the steps preceding the release of free acetaldehyde.

Acetaldehyde↗
PubMed1979

Regulation of mitochondrial pyruvate carboxylation and gluconeogenesis in rat hepatocytes via an alpha-adrenergic, adenosine 3':5'-monophosphate-independent mechanism.

Experiments were performed to determine if catecholamines can regulate control points in the gluconeogenic pathway, such as mitochondrial pyruvate carboxylation and pyruvate kinase activity, via an alpha-adrenergic, adenosine 3':5'-monophosphate-independent mechanism. Of a number of alpha agonists tested, only norepinephrine, epinephrine, and phenylephrine caused an increase in mitochondrial pyruvate metabolism. The effects of catecholamines on pyruvate carboxylation were not attenuated by 1-propranolol which abolishes changes in cyclic nucleotide levels but were blocked by alpha antagonists such as ergotamine, phenoxybenzamine, and phentolamine. Time course experiments demonstrated that the effects of catecholamines on the mitochondria and on carbohydrate metabolism correlated temporally with the concentration of epinephrine in the medium but not with the small changes in adenosine 3':5'-monophosphate. The effects of catecholamines appeared to require extracellular Ca2+ ion. The observation that catecholamines do not increase gluconeogenesis to the same extent as glucagon was not due to a differential effect on mitochondrial CO2 fixation. Rather, catecholamines caused a smaller inhibition of pyruvate kinase activity than did glucagon. The effects of catecholamines on pyruvate kinase also appeared to be mediated by an alpha-adrenergic, adenosine 3':5'-monophosphate-independent mechanism.

Adrenergic alpha-Agonists↗
PubMed1984

The molecular basis for the two different clinical presentations of classical pyruvate carboxylase deficiency.

Eight cases of isolated human pyruvate carboxylase deficiency were examined from seven families. Although all patients presented with a chronic lacticacidemia, two particular patients presented with the added features of hyperammonemia, citrullinemia, and hyperlysinemia. When cultured skin fibroblasts from these patients were examined for their ability to synthesize [3H]biotin-containing proteins, it was found that the two patients who presented with hyperammonemia, citrullinemia, and hyperlysinemia did not synthesise a protein of the correct subunit molecular weight (Mr = 125 K daltons) corresponding to pyruvate carboxylase. In addition, when skin fibroblast proteins were labeled with [35S]methionine, cross-reacting material (CRM) corresponding to pyruvate carboxylase was immunoprecipitated by antipyruvate carboxylase antiserum in most patients, but again the two patients with the atypical presentation showed no CRM. We propose that the different clinical presentation of human pyruvate carboxylase deficiency is a manifestation of two different mutations in the pyruvate carboxylase gene, one that results in the synthesis of a relatively inactive pyruvate carboxylase protein CRM(+ve) and one that results in the lack of expression of the gene in the form of a recognizable protein CRM(-ve).

Biotin↗