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PubMed1982

Biochemical diversity for biosynthesis of aromatic amino acids among the cyanobacteria.

We examined the enzymology and regulatory patterns of the aromatic amino acid pathway in 48 strains of cyanobacteria including representatives from each of the five major grouping. Extensive diversity was found in allosteric inhibition patterns of 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase, not only between the major groupings but also within several of the generic groupings. Unimetabolite inhibition by phenylalanine occurred in approximately half of the strains examined; in the other strains unimetabolite inhibition by tyrosine and cumulative, concerted, and additive patterns were found. The additive patterns suggest the presence of regulatory isozymes. Even though both arogenate and prephenate dehydrogenase activities were found in some strains, it seems clear that the arogenate pathway to tyrosine is a common trait that has been highly conserved among cyanobacteria. No arogenate dehydratase activities were found. In general, prephenate dehydratase activities were activated by tyrosine and inhibited by phenylalanine. Chorismate mutase, arogenate dehydrogenase, and shikimate dehydrogenase were nearly always unregulated. Most strains preferred NADP as the cofactor for the dehydrogenase activities. The diversity in the allosteric inhibition patterns for 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase, cofactor specificities, and the presence or absence of prephenate dehydrogenase activity allowed the separation of subgroupings within several of the form genera, namely, Synechococcus, Synechocystis, Anabaena, Nostoc, and Calothrix.

3-Deoxy-7-Phosphoheptulonate Synthase↗

PubMed1984

Regulation of phenylalanine biosynthesis in Rhodotorula glutinis.

The phenylalanine biosynthetic pathway in the yeast Rhodotorula glutinis was examined, and the following results were obtained. (i) 3-Deoxy-D-arabinoheptulosonate-7-phosphate (DAHP) synthase in crude extracts was partially inhibited by tyrosine, tryptophan, or phenylalanine. In the presence of all three aromatic amino acids an additive pattern of enzyme inhibition was observed, suggesting the existence of three differentially regulated species of DAHP synthase. Two distinctly regulated isozymes inhibited by tyrosine or tryptophan and designated DAHP synthase-Tyr and DAHP synthase-Trp, respectively, were resolved by DEAE-Sephacel chromatography, along with a third labile activity inhibited by phenylalanine tentatively identified as DAHP synthase-Phe. The tyrosine and tryptophan isozymes were relatively stable and were inhibited 80 and 90% by 50 microM of the respective amino acids. DAHP synthase-Phe, however, proved to be an extremely labile activity, thereby preventing any detailed regulatory studies on the partially purified enzyme. (ii) Two species of chorismate mutase, designated CMI and CMII, were resolved in the same chromatographic step. The activity of CMI was inhibited by tyrosine and stimulated by tryptophan, whereas CMII appeared to be unregulated. (iii) Single species of prephenate dehydratase and phenylpyruvate aminotransferase were observed. Interestingly, the branch-point enzyme prephenate dehydratase was not inhibited by phenylalanine or affected by tyrosine, tryptophan, or both. (iv) The only site for control of phenylalanine biosynthesis appeared to be DAHP synthase-Phe. This is apparently sufficient since a spontaneous mutant, designated FP9, resistant to the growth-inhibitory phenylalanine analog p-fluorophenylalanine contained a feedback-resistant DAHP synthase-Phe and cross-fed a phenylalanine auxotroph of Bacillus subtilis.

3-Deoxy-7-Phosphoheptulonate Synthase↗

PubMed1987

Control of glycolysis by glyceraldehyde-3-phosphate dehydrogenase in Streptococcus cremoris and Streptococcus lactis.

The decreased response of the energy metabolism of lactose-starved Streptococcus cremoris upon readdition of lactose is caused by a decrease of the glycolytic activity (B. Poolman, E. J. Smid, and W. N. Konings, J. Bacteriol. 169:1460-1468, 1987). The decrease in glycolysis is accompanied by a decrease in the activities of glyceraldehyde-3-phosphate dehydrogenase and phosphoglycerate mutase. The steady-state levels of pathway intermediates upon refeeding with lactose after various periods of starvation indicate that the decreased glycolysis is primarily due to diminished glyceraldehyde-3-phosphate dehydrogenase activity. Furthermore, quantification of the control strength exerted by glyceraldehyde-3-phosphate dehydrogenase on the overall activity of the glycolytic pathway shows that this enzyme can be significantly rate limiting in nongrowing cells.

Energy Metabolism↗

PubMed1994

The mutation DGT1-1 decreases glucose transport and alleviates carbon catabolite repression in Saccharomyces cerevisiae.

Glucose in ethanol-glycerol mixtures inhibits growth of Saccharomyces cerevisiae mutants lacking phosphoglycerate mutase. A suppressor mutation that relieved glucose inhibition was isolated. This mutation, DGT1-1 (decreasing glucose transport), was dominant and produced pleiotropic effects even in an otherwise wild-type background. Growth of the DGT1-1 mutant in glucose was dependent on respiration, and no ethanol was detected in the medium within 7 h of glucose addition. When grown on glucose, the mutant had a reduced glucose uptake and both the low- and high-affinity transport systems were affected. In galactose-grown cells, only the high-affinity glucose transport system was detected. This system had similar kinetic characteristics in the wild type and in the mutant. Catabolite repression of several enzymes was absent in the mutant during growth in glucose but not during growth in galactose. In contrast with the wild type, the mutant grown in glucose had high transcription of the glucose transporter gene SNF3 and no transcription of HXT1 and HXT3. Expression of multicopy plasmids carrying the HXT1, HXT2, or HXT3 gene allowed partial recovery of both fermentative capacity and catabolite repression in the mutant. The results suggest that DGT1 codes for a regulator of the expression of glucose transport genes. They also suggest that glucose flux might determine the levels of molecules implicated as signals in catbolite repression.

Biological Transport↗

PubMed2000

Prephenate dehydratase from the aphid endosymbiont (Buchnera) displays changes in the regulatory domain that suggest its desensitization to inhibition by phenylalanine.

Buchnera aphidicola, the prokaryotic endosymbiont of aphids, complements dietary deficiencies with the synthesis and provision of several essential amino acids. We have cloned and sequenced a region of the genome of B. aphidicola isolated from Acyrthosiphon pisum which includes the two-domain aroQ/pheA gene. This gene encodes the bifunctional chorismate mutase-prephenate dehydratase protein, which plays a central role in L-phenylalanine biosynthesis. Two changes involved in the overproduction of this amino acid have been detected. First, the absence of an attenuator region suggests a constitutive expression of this gene. Second, the regulatory domain of the Buchnera prephenate dehydratase shows changes in the ESRP sequence, which is involved in the allosteric binding of phenylalanine and is strongly conserved in prephenate dehydratase proteins from practically all known organisms. These changes suggest the desensitization of the enzyme to inhibition by phenylalanine and would permit the bacterial endosymbiont to overproduce phenylalanine.

Amino Acid Sequence↗

PubMed2002

Glyoxylate regeneration pathway in the methylotroph Methylobacterium extorquens AM1.

Most serine cycle methylotrophic bacteria lack isocitrate lyase and convert acetyl coenzyme A (acetyl-CoA) to glyoxylate via a novel pathway thought to involve butyryl-CoA and propionyl-CoA as intermediates. In this study we have used a genome analysis approach followed by mutation to test a number of genes for involvement in this novel pathway. We show that methylmalonyl-CoA mutase, an R-specific crotonase, isobutyryl-CoA dehydrogenase, and a GTPase are involved in glyoxylate regeneration. We also monitored the fate of (14)C-labeled carbon originating from acetate, butyrate, or bicarbonate in mutants defective in glyoxylate regeneration and identified new potential intermediates in the pathway: ethylmalonyl-CoA, methylsuccinyl-CoA, isobutyryl-CoA, methacrylyl-CoA, and beta-hydroxyisobutyryl-CoA. A new scheme for the pathway is proposed based on these data.

Acyl Coenzyme A↗

PubMed1995

The yeast Mcm1 protein is regulated posttranscriptionally by the flux of glycolysis.

Mcm1 is a multifunctional protein which plays a role both in the initiation of DNA replication and in the transcriptional regulation of diverse genes in Saccharomyces cerevisiae. The mcm1-1 mutation results in instability of minichromosomes and alpha-specific sterility. Second-site suppressors that restore minichromosome stability but not fertility to the mcm1-1 mutant were isolated. Two of the suppressors, pgm1-1 and pgm1-2, are mutant alleles of PGM1 which encodes a glycolytic enzyme, phosphoglycerate mutase. We show that the pgm1-1 mutation suppresses the minichromosome maintenance (Mcm) defect by increasing the protein activity or level of Mcm1-1 posttranscriptionally. This increase in the intracellular Mcm1-1 activity is sufficient to suppress the Mcm defect but only minimally suppresses the mating defect. Mutations in genes encoding other glycolytic enzymes, such as eno2::URA3, can also suppress the Mcm phenotype of mcm1-1. Suppression by these glycolytic enzyme mutations correlates with a reduced rate of glycolysis rather than a reduced rate of cell growth. This study suggests that in response to changes in their nutritional states yeast cells may attain homeostasis by modulating the activity of global regulators like Mcm1, which plays a central role in the regulation of energy-expensive anabolic processes.

Alleles↗

PubMed2006

Molecular dynamics simulation of interactions in glycolytic enzymes.

Two glycolytic enzymes, phosphoglycerate mutase (PGM) and enolase from Saccharomyces cerevisiae, have been chosen to detect complex formation and possible channeling, using molecular dynamics simulation. The enzymes were separated by 10 angstroms distance and placed in a water-filled box of size 173 x 173 x 173 angstroms. Three different orientations have been investigated. The two initial 3-phosphoglycerate substrate molecules near the active centers of the initial structure of PGM have been replaced with final product (2-phosphoglycerate) molecules, and 150 mM NaCl together with three Mg2+ ions have been added to the system to observe post-catalytic activity under near-physiological conditions. Analysis of interaction energies and conformation changes for 3 nsec simulation indicates that PGM and enolase do show binding affinity between their near active regions, which is necessary for channeling to occur. Interaction of the C-terminal residues Ala239 and Val240 of PGM (which partially "cap" the 2-phosphoglycerate) with enolase also favors the existence of channeling.

Binding Sites↗

PubMed1982

Isozyme patterns and protein profiles in neuromuscular disorders.

The isozyme patterns of six different enzymes and the polypeptide profiles of soluble proteins have been examined in muscle biopsy specimens from 74 patients with a wide variety of neuromuscular disorders. About half of the samples showed unusual features in at least one, and often several, of the enzymes and proteins tested. The extent of the biochemical abnormalities was roughly proportional to the severity of the disorders. In all cases the unusual isozymes and polypeptide profiles seemed to reflect a reversion to the fetal pattern of gene expression. However, this change appeared to occur in extant muscle and was not dependent on the appearance of new muscle fibres. Among the enzymes, phosphoglycerate mutase followed by creatine kinase appeared to be the most sensitive index of muscle disorder. The extent of the change in the muscle creatine kinase isozyme pattern was not correlated with the levels of serum creatine kinase activity.

Acid Phosphatase↗

PubMed2000

Complementation studies in the cblA class of inborn error of cobalamin metabolism: evidence for interallelic complementation and for a new complementation class (cblH).

AIM: To investigate genetic heterogeneity within the cblA class of inborn error of cobalamin metabolism. CONTEXT: The cblA disorder is characterised by vitamin B12 (cobalamin) responsive methylmalonic aciduria and deficient synthesis of adenosylcobalamin, required for activity of the mitochondrial enzyme methylmalonyl CoA mutase. The cblA gene has not been identified or cloned. We have previously described a patient with the clinical and biochemical phenotype of the cblA disorder whose fibroblasts complemented cells from patients with all known types of inborn error of adenosylcobalamin synthesis, including cblA. METHODS: We have performed somatic cell complementation analysis of the cblA variant fibroblast line with a panel of 28 cblA lines. We have also performed detailed complementation analysis on a panel of 10 cblA fibroblast lines, not including the cblA variant line. RESULTS: The cblA variant line complemented all 28 cell lines of the panel. There was evidence for interallelic complementation among the 10 cblA lines used for detailed complementation analysis; no cell line in this panel complemented all other members. CONCLUSIONS: These results strongly suggest that the cblA variant represents a novel complementation class, which we have designated cblH and which represents a mutation at a distinct gene. They also suggest that the cblA gene encodes a protein that functions as a multimer, allowing for extensive interallelic complementation.

Alleles↗

PubMed1992

Cobalamin deficiency and the pathogenesis of nervous system disease.

Neuropathy commonly complicates cobalamin (Cb1) deficiency in humans, monkeys, fruit bats, and pigs. The neuropathy is characterized by demyelination of the posterolateral columns of the spinal cord (subacute combined degeneration). The lesion was thought to arise primarily from impairment of the adenosylcobalamin-dependent methylmalonyl CoA mutase reaction, leading to the formation of abnormal odd-chain and branched-chain fatty acids and their incorporation into myelin with resultant demyelination. Data from recently developed animal models of the Cb1 neuropathy induced by exposure to nitrous oxide do not substantiate this hypothesis, but rather identify impairment of the methylcobalamin-dependent methionine synthetase reaction as the more important basic defect. The key evidence for this hypothesis is the ability of methionine to delay the onset of Cb1 neuropathy in experimental Cb1 deficiency. In the Cb1-deficient pig, adenosylhomocysteine accumulates in neural tissue, presumably owing to the inability to recycle homocysteine via the defective methionine synthetase reaction. Accumulation of adenosylhomocysteine results in a fall in the adenosylmethionine:adenosylhomocysteine methylation ratio, and this change is believed to cause defective methylation and demyelination in the nervous system. However, in the Cb1 neuropathy in the fruit bat, adenosylhomocysteine does not accumulate in the nervous system, the methylation ratio does not change, and no defect can be demonstrated in the methylation of myelin lipid or basic protein. Although a central role for methionine in the pathogenesis of the Cb1 neuropathy has been established, defective methylation attendant upon impairment of the methionine synthetase reaction may not be the universal defect underlying the Cb1 neuropathy. This would suggest that the methionine effect could be mediated via its role in formate metabolism or polyamine synthesis, or by some as yet unidentified pathway.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1982

Postnatal regulation of canine oxygen delivery: control of erythrocyte 2,3-DPG levels.

The oxygen affinity of canine blood changes markedly following birth. These changes are correlated with alterations in the intracellular concentration of 2,3-diphosphoglycerate (2,3-DPG). We have examined the control of erythrocyte glycolysis by measurements of intracellular enzymes and intermediates, and we have identified the component responsible for regulation of 2,3-DPG concentration and hence blood oxygen affinity during canine postnatal development. The concentration of 2,3-DPG could be regulated entirely by the enzymes of the Rapoport-Luebering shunt. We have not detected any alterations in the levels or intracellular activity of 2,3-DPG mutase or 2,3-DPG phosphatase during development; therefore postnatal changes of 2,3-DPG must be a result of changes in the intracellular concentrations of 1,3-diphosphoglycerate (1,3-DPG) that are controlled by other reactions in the glycolytic pathway. Neither low intracellular concentrations of glucose, the glycolytic substrate, nor an inherently low glycolytic rate can account for the low 2,3-DPG levels at birth. 1,3-DPG concentrations and hence 2,3-DPG concentrations are controlled by the activity of pyruvate kinase, which acts as a glycolytic sink reaction. The intracellular activity of pyruvate kinase decreases during the first 50-60 days of age and causes the accumulation of 2,3-DPG. There is a subsequent change in the in vivo kinetic properties of the enzyme, giving increased intracellular activity and resulting in the slow decline of 2,3-DPG concentrations toward normal adult values.

2,3-Diphosphoglycerate↗

PubMed1983

Postnatal regulation of 2,3-DPG in sheep erythrocytes.

The erythrocyte 2,3-diphosphoglycerate (2,3-DPG) concentrations of sheep change markedly during the 1st mo following birth. From measurements of erythrocyte glycolytic enzymes and intermediate concentrations, we have identified the mechanism regulating erythrocyte 2,3-DPG in postnatal sheep. The postnatal changes in erythrocyte 2,3-DPG do not result from qualitative or quantitative changes in the intracellular activities of the Rapoport-Luebering shunt enzymes, 2,3-DPG mutase or 2,3-DPG phosphatase. The postnatal 2,3-DPG changes result from changes in the erythrocyte concentration of 1,3-DPG, which is controlled by other reactions in the glycolytic pathway. Neither changes in the glycolytic control enzymes (hexokinase, phosphofructokinase, and pyruvate kinase) nor changes in the intrinsic glycolytic rate can account for these 1,3-DPG concentration changes. 1,3-DPG concentrations are regulated by the in vivo glycolytic rate, which is controlled by the intracellular concentration of glucose, the glycolytic substrate. Glucose concentrations are 0.3 mmol/l cells in erythrocytes of fetal sheep (135-140 days gestational age), increase following birth to a peak of 3.8 mmol/l cells by the 1st wk of age, and then decline to the normal adult levels of 0.5 mmol/l cells by the end of the 1st mo.

2,3-Diphosphoglycerate↗

PubMed1987

Glycolytic regulation during an aerobic rest-to-work transition in dog gracilis muscle.

Glycogen phosphorylase activity and several glycolytic intermediates were measured at rest and after 5, 10, 15, 30, 60, and 180 s of twitch stimulation at 4 Hz in fast-frozen samples of gracilis muscle. During an initial burst of glycolysis (0-5 s) only 3-phosphoglycerate and lactate accumulate. These changes are reversed during the period of low glycolytic flux (5-30 s). During a second burst of glycolysis (30-60 s) most glycolytic intermediates increase. The levels of glycogen phosphorylase a changes in parallel with the initial burst of glycolysis but remain at resting levels throughout the second burst. The phosphoglycerate mutase-enolase steps deviate from equilibrium during the initial burst of glycolysis, suggesting a transiently rate-limiting role. Analysis using a model of phosphofructokinase kinetics indicates that combined changes in cytosolic pH (R. J. Connett, J. Appl. Physiol. 63: 2360-2365, 1987) and free [ADP] and [AMP] can account for the initial burst of glycolysis. The second burst of glycolysis requires other regulatory factors. It is concluded that an initial alkalization is a major regulatory factor in the early burst of glycolysis during a rest-to-work transition in red muscle.

Animals↗

PubMed1999

PGAM-M expression is regulated pretranslationally in hindlimb muscles and under altered loading conditions.

Enzymatic activity from the muscle-specific isoform of phosphoglycerate mutase (PGAM-M) is higher within glycolytic skeletal muscles than in oxidative muscles. The hypothesis that PGAM-M is regulated pretranslationally among muscles of the hindlimb was tested using enzymatic assays, Western blots, and Northern blots. We further investigated the regulatory level(s) at which PGAM-M gene expression is controlled during hindlimb unweighting. PGAM-M mRNA and immunoreactive protein levels were fourfold lower in the rat soleus muscle than in the tibialis anterior (TA), plantaris, and extensor digitorum longus muscles. Four weeks of unweighting induced a 2.5-fold increase in PGAM enzymatic activity within the soleus muscle, a 1.8-fold increase in PGAM-M immunoreactivity, and a 3. 5-fold increase in PGAM-M mRNA. To examine potential transcriptional regulatory mechanisms, the proximal 400 bp of the rat PGAM-M promoter were linked to a firefly luciferase and injected into normal and unweighted TA and soleus muscles. Firefly luciferase activity was elevated two- to threefold in the TA and the unweighted soleus over the normal soleus muscle. These data suggest that PGAM-M expression is pretranslationally regulated among muscle types and within unweighted slow-twitch muscle. Furthermore, the proximal 400 bp of the PGAM-M promoter contains cis-acting sequences to allow muscle-type-specific expression of a reporter gene and responsiveness to soleus muscle unweighting.

Animals↗

PubMed1981

Nitrous oxide has multiple deleterious effects on cobalamin metabolism and causes decreases in activities of both mammalian cobalamin-dependent enzymes in rats.

In man, use of the general anesthetic nitrous oxide, N2O, is associated with hematologic and neurologic abnormalities that mimic those seen in cobalamin (Cbl, vitamin B12) deficiency. We have measured a number of aspects of Cbl metabolism in rts exposed to various concentrations of N2O for various periods of time. As little as 2% N2O given for 15 h resulted in 30% inhibition of methionine synthetase (MS) in rat liver. With 50% N2O, inhibition of 70% occurred with 1 h and did not change during the next 48 h. Under these conditions, no inhibition of methylmalonyl-CoA mutase (MMCoAM) was observed. The recovery of MS activity was slow and was only 80% of control values 72 h after N2O was stopped. Studies employing rats previously injected with [57Co]Cbl showed that N2O displaced [57Co]Cbl from MS in a manner that temporally and quantitatively paralleled the loss of MS activity. Recovery of MS activity paralleled the reappearance of [57Co]Cbl on MS. N2O also caused the hepatic content of CH3-[57Co]Cbl to decrease by 20-60%. When [57Co]-Cbl was extracted from liver and analyzed by paper chromatography, [57Co]Cbl analogues were present (10-40% of total [57Co]Cbl) in rats exposed to N2O, but not in control animals. When rats were exposed to 50% N2O for 33 d, the total of endogenous Cbl and Cbl analogues in liver decreased to 35% of control values and endogenous Cbl decreased to 10% of control values. At this time, MS activity was 15% of control values and MMCoAM was only 26% of control values. We conclude that N2O causes multiple defects in Cbl metabolism that include the following: (a) rapid inhibition of MS activity with a slow recovery when N2O is stopped; (b) displacement of Cbl from MS; (c) decreased CH3-Cbl; (d) conversion of Cbl to Cbl analogues; (e) the gradual development of Cbl deficiency and (f) an eventual decrease in MMCoAM activity with a further decrease in MS activity.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1991

Inhibition of cobalamin-dependent enzymes by cobalamin analogues in rats.

To determine which parts of the cobalamin (cbl) molecule are required for enzyme activity and which parts, if altered, might inhibit cbl-dependent enzyme activity, we synthesized 16 cbl analogues and administered them to nutritionally normal rats. The cbl analogues, with either modifications of the propionamide side chains of the A-, B-, and C-rings, the acetamide side chain of the B-ring, or the nucleotide moiety, were administered to rats by continuous 14-d subcutaneous infusion. Infusion of cbl-stimulated, cbl-dependent activity. Changes in any part of the cbl molecule always abolished stimulation and, in some cases, caused potent inhibition of both cbl-dependent enzymes. The most inhibitory analogues, OH-cbl[c-lactam], a B-ring analogue, and OH-cbl[e-dimethylamide] and OH-cbl[e-methylamide], two C-ring analogues, decreased mean liver holo-L-methylmalonyl-coenzyme A mutase activity to 65% of control values and increased serum methylmalonic acid concentrations to as high as 3,200% of the control values. Liver methionine synthetase activity was decreased to approximately 20% of the control and mean serum total homocysteine concentrations were increased to 340% of control. A similar level of inhibition was demonstrated in rats who were exposed to 28 d of inhaled nitrous oxide or a prolonged period of dietary cbl deficiency. The inhibitory cbl analogues, nitrous oxide, and diet deficiency all depleted liver cbl. The naturally occurring cbl analogues with modifications of the nucleotide moiety had no effects. We conclude that all parts of the cbl molecule are necessary for in vivo cbl-dependent enzyme activity and that modifications of the side chains of the B and C rings are associated with potent in vivo inhibition of cbl-dependent enzyme activity.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗

PubMed1994

Cloning and expression of mutations demonstrating intragenic complementation in mut0 methylmalonic aciduria.

The mut0 mutation resulting in methylmalonyl CoA mutase (MCM) apoenzyme deficiency and methylmalonic aciduria is characterized by undetectable enzyme activity in cell extracts and low incorporation of propionate into cultured cells which is not stimulated by hydroxycobalamin. A mut0 fibroblast cell line (WG1681) from an African-American male infant complemented another mut0 cell line (WG 1130). Cloning and sequencing of cDNA from WG 1681 demonstrated compound heterozygosity for two novel changes at highly conserved sites: G623R and G703R. In addition, two previously described homozygous polymorphisms, H532R and V671I, were found. Hybridization of allele-specific oligonucleotides to PCR amplified MCM exons from the proband and family members identified a clinically normal mother, half-sister, and half-brother as carriers of the G703R change in cis with both polymorphisms. Transfection of each change into a mut0 cell line with very low MCM mRNA (GM1673) demonstrated a lack of stimulation of propionate uptake in the absence and presence of hydroxycobalamin. Cotransfection of each mutation with the previously identified R93H mutation of WG 1130 stimulated propionate uptake, indicating that G623R and G703R are independently capable of complementing the R93H mutation.

Base Sequence↗