[Formiminotransferase deficiency syndrome].
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Formiminoglutamic Acid↗
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Folate-responsive homocystinuria and megaloblastic anaemia in a female patient with functional methionine synthase deficiency (cblE disease).
This first detailed report of a female patient with functional methionine synthase deficiency due to the cblE defect describes treatment with several vitamins and cofactors and clinical progress for 17 years. Before treatment, major findings were microcephaly, psychomotor retardation, episodic reduced consciousness, megaloblastic anaemia, increased plasma free homocystine (> 20 mumol/L), low plasma methionine (< 10 mumol/L) and increased excretion of formiminoglutamate. On high-dose folic acid, biochemical abnormalities such as formiminoglutamate excretion and homocystinuria nearly normalized, but clinical and haematological abnormalities remained. On replacement of folate with methylcobalamin, alertness, motor function, speech and the electroencephalogram improved, biochemical features were similar, but the mean corpuscular volume increased. The best control was observed on a combination of folate and methylcobalamin. At 17 years of age she remains severely mentally retarded. In cultured fibroblasts methionine synthesis was reduced (0.03 nmol/mg/per 16 h, controls 2.4-6.9); methionine synthase activity was normal under high reducing conditions but decreased on limiting the reducing agent, dithiothreitol, to 5 mmol/L (18% of total, controls 51-81%); formation of methylcobalamin was low (4.5% of total cobalamins, control 57.5%) and complementation studies indicated the cblE defect. Methionine formation showed only minor increases in cells grown in folate- or cobalamin-supplemented medium. Serine synthesis, which was low in normal medium, increased with cobalamin supplementation. These studies suggest further heterogeneity within cblE mutants, show the difficulty of establishing the enzyme defect in vitro, and indicate a role for folate in addition to cobalamin in treatment.
5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
The regulation of folate and methionine metabolism.
1. The isolated perfused rat liver and suspensions of isolated rat hepatocytes fail to form glucose from histidine, in contrast with the liver in vivo. Both rat liver preparations readily metabolize histidine. The main end product is N-formiminoglutamate. In this respect the liver preparations behave like the liver of cobalamin- or folate-deficient mammals. 2. Additions of L-methionine in physiological concentrations (or of ethionine [2-amino-4-(ethylthio)butyric acid]) promotes the degradation of formiminoglutamate, as is already known to be the case in cobalamin of folate deficiency. Added methionine also promotes glucose formation from histidine. 3. Addition of methionine accelerates the oxidation of formate to bicarbonate by hepatocytes. 4. A feature common to cobalamin-deficient liver and the isolated liver preparations is taken to be a low tissue methionine concentration, to be expected in cobalamin deficiency through a decreased synthesis of methionine and caused in liver preparations by a washing out of amino acids during the handling of the tissue. 5. The available evidence is in accordance with the assumption that methionine does not directly increase the catalytic capacity of formyltetrahydrofolate dehydrogenase; rather, that an increased methionine concentration raises the concentration of S-adenosylmethionine, thus leading to the inhibition of methylenetetrahydrofolate reductase activity [Kutzbach & Stokstad (1967) Biochim. Biophys. Acta 139, 217-220; Kutzbach & Stokstad (1971) Methods Enzymol. 18B, 793-798], that this inhibition causes an increase in the concentration of methylenetetrahydrofolate and the C1 tetrahydrofolate derivatives in equilibrium with methylenetetrahydrofolate, including 10-formyltetrahydrofolate; that the increased concentration of the latter accelerates the formyltetrahydrofolate dehydrogenase reaction, because the normal concentration of the substrate is far below the Km value of the enzyme for the substrate. 6. The findings are relevant to the understanding of the regulation of both folate and methionine metabolism. When the methionine concentration is low, C1 units are preserved by the decreased activity of formyltetrahydrofolate dehydrogenase and are utilized for the synthesis of methionine, purines and pyrimidines. On the other hand when the concentration of methionine, and hence adenosylmethionine, is high and there is a surplus of C1 units as a result of excess of dietary supply, formyltetrahydrofolate dehydrogenase disposes of the excess. When ample dietary supply causes an excess of methionine, which has to be disposed of by degradation, the increased activity of formyltetrahydrofolate dehydrogenase decreases the supply of methyltetrahydrofolate. Thus homocysteine, instead of being remethylated, enters the pathway of degradation via cystathionine. 7. The findings throw light on the biochemical abnormalities associated with cobalamin deficiency (megaloblastic anaemia), especially on the 'methylfolate-trap hypothesis'. This is discussed. 8...
Amino Acids↗
The crystal structure of the formiminotransferase domain of formiminotransferase-cyclodeaminase: implications for substrate channeling in a bifunctional enzyme.
BACKGROUND: The bifunctional enzyme formiminotransferase-cyclodeaminase (FTCD) contains two active sites at different positions on the protein structure. The enzyme binds a gamma-linked polyglutamylated form of the tetrahydrofolate substrate and channels the product of the transferase reaction from the transferase active site to the cyclodeaminase active site. Structural studies of this bifunctional enzyme and its monofunctional domains will provide insight into the mechanism of substrate channeling and the two catalytic reactions. RESULTS: The crystal structure of the formiminotransferase (FT) domain of FTCD has been determined in the presence of a product analog, folinic acid. The overall structure shows that the FT domain comprises two subdomains that adopt a novel alpha/beta fold. Inspection of the folinic acid binding site reveals an electrostatic tunnel traversing the width of the molecule. The distribution of charged residues in the tunnel provides insight into the possible mode of substrate binding and channeling. The electron density reveals that the non-natural stereoisomer, (6R)-folinic acid, binds to the protein; this observation suggests a mechanism for product release. In addition, a single molecule of glycerol is bound to the enzyme and indicates a putative binding site for formiminoglutamate. CONCLUSIONS: The structure of the FT domain in the presence of folinic acid reveals a possible novel mechanism for substrate channeling. The position of the folinic acid and a bound glycerol molecule near to the sidechain of His82 suggests that this residue may act as the catalytic base required for the formiminotransferase mechanism.
Ammonia-Lyases↗
Disruption of histidine catabolism in NEUT2 mice.
Homozygous NEUT2 mice lack cytosolic 10-formyltetrahydrofolate dehydrogenase (FDH; Champion et al. (1994) Proc. Natl. Acad. Sci. USA 91, 11,338-11,342) and as a consequence should be unable to oxidize carbon 2 of l-histidine to CO2 via 10-formyltetrahydrofolate in liver cytosol. There was essentially no oxidation of l-[2-14C]histidine to 14CO2 in homozygous NEUT2 mice, but 52% of the [2-14C]l-histidine dose was recovered in the urine within 24 h. Analysis of urine samples for [14C]formiminoglutamate, the expected excretion product, was negative; however, [14C]urocanic acid was detected. Investigation of histidine catabolism via the folate-dependent deamination pathway revealed no detectable urocanase activity in homozygous NEUT2 mice, while heterozygous NEUT2 mice had 50% urocanase activity compared to normal mice. Histidase and formiminotransferase-cyclodeaminase, also on the histidine deamination pathway, had similar specific activities in normal and NEUT2 mice. Histidine-pyruvate aminotransferase, the first enzyme of the alternate histidine transamination catabolic pathway did not appear to be affected by the loss of urocanase. Based on the excretion of urocanic acid it is estimated that NEUT2 mice catabolize approximately 40 micromol/day via the deamination pathway. The loss of urocanase activity in homozygous NEUT2 mice may allow these mice to survive the disruption in folate metabolism by sparing the liver cytosolic tetrahydrofolate pool.
Animals↗
Kinetics of amino acid transport across bone marrow cell membranes.
Dog bone marrow nucleated cells were incubated in media containing labeled L-amino acids, and the cellular accumulation of radioactivity as a function of time was measured and analyzed according to a three-compartment model.(a) The turnover half-time of intracellular histidine arising from extracellular sources was 6.0 +/-0.7 (SEM) min. Similar turnover half-time for serine was 10 +/-2 (SEM) min; for tryptophan, 6.5 +/-1.2 (SEM) min; and for methionine, 4.4 +/-0.6 (SEM) min. Loss of the intracellular amino acids to the extracellular space accounted for the major portion of their turnover.(b) Each of the four amino acids noted above appeared to be actively transported into the cell.(c) At physiologic extracellular histidine concentrations, histidine entered the cell predominantly by a facilitated process with an apparent Michaelis constant of 0.28 mmole/liter and a limiting flux of 14 x 10(-8) mmumole/min per cell. Loss of histidine from the cell appeared to be substantially facilitated with an apparent Michaelis constant greater than that for histidine entry.(d) Insulin and glucagon had no measurable effect on histidine transport across the bone marrow cell membrane.(e) Methionine depressed the influx and the fractional turnover rate of the intracellular pool of both histidine and serine.(f) The extent of cellular accumulation of alpha-N-formiminoglutamate and alpha-N-formylglutamate was about 1/100 that of histidine. alpha-N-formiminoglutamate added to the culture was about (1/4) as effective as histidine in providing monocarbon fragments for DNA thymine synthesis.
Amino Acids↗
Mental retardation with hyperfolic-acidemia not associated with formiminoglutamic-acciduria: cyclohydrolase deficiency syndrome.
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Child, Preschool↗
"HYPERFOLIC-ACIDEMIA WITH FORMIMINOGLUTAMIC-ACIDURIA FOLLOWING HISTIDINE LOADING". SUGGESTED FOR A CASE OF CONGENITAL DEFICIENCY IN FORMIMINOTRANSFERASE.
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Blood↗
Cloning and sequencing of a 29 kb region of the Bacillus subtilis genome containing the hut and wapA loci.
Within the framework of an international project for the sequencing of the entire Bacillus subtilis genome, a 29 kb chromosome segment, which contains the hut operon (335 degrees) and the wapA gene, has been cloned and sequenced. This region (28,954 bp) contains 21 complete ORFs and one partial one. The 5th, 6th and 17th genes correspond to hutH encoding histidase, hutP encoding the positive regulator for the hut operon and wapA encoding a precursor of three major wall-associated proteins, respectively. A homology search for their products deduced from the 21 complete ORFs revealed that nine of them exhibit significant homology to known proteins such as urocanase (Pseudomonas putida), a protein involved in clavulanic acid biosynthesis (Streptomyces griseus), amino acid permeases (lysine, Escherichia coli; histidine, Saccharomyces cerevisiae; and others), beta-glucoside-specific phosphotransferases (E. coli and Erwinia chrysanthemi) and 6-phospho-beta-glucosidases (E. coli and Erw. chrysanthemi). Based on the features of the determined sequence and the results of the homology search, as well as on genetic data and sequence of the hut genes reported by other groups, it is predicted that the B. subtilis hut operon may consist of the following six genes (6th-1st), the last of which is followed by a typical rho-independent transcription terminator: hutP, hutH, EE57A (hutU) encoding urocanase, EE57B (hutI) encoding imidazolone-5-propionate hydrolase, EE57C (hutG) encoding formiminoglutamate hydrolase and EE57D (tentatively designated as hutM) possibly encoding histidine permease. Interestingly, the direction of transcription of these hut genes is opposite to that of the movement of the replication fork.
ATP-Binding Cassette Transporters↗
Folate deficiency in the livers of diethylnitrosaminetreated rats.
The effects of diethylnitrosamine on the metabolism of folic acid and related compounds in rat liver were investigated. The administration, in the drinking water, of diethynitrosamine to rats for 3 weeks led to decreased hepatic levels of folate, S-adenosylmethionine, and 5-methyltetrahydrofolate:homocysteine methyltransferase. Liver methylenetetrahydrofolate reductase levels were unaffected by administration of diethylnitrosamine. The polyglutamate fraction of hepatic folates obtained from rats treated with diethylnitrosamine for 3 weeks prior to injection with [3H]folate contained less radioactivity than did the polyglutamate fraction obtained from the livers of control rats treated with [3H]folate alone. Similarly, the polyglutamate folate fraction of rat livers that were simultaneously perfused with both diethylnitrosamine and [3H]folate contained less label than the polyglutamate fraction of rat livers perfused with [3H]folate only. Livers perfused with [2-14C]histidine and diethylnitrosamine produced more formiminoglutamate and less CO2 than livers treated with [2-14C]histidine only. The changes noted in the hepatic folate metabolism of diethylnitrosamine-treated rats resemble those seen in the livers of methyl-deficient rats.
Animals↗
Folic acid metabolism in vitamin B12-deficient sheep. Depletion of liver folates.
1. Metabolism of folate was studied in six ewes in an advanced state of vitamin B(12) deficiency as judged by voluntary food intake and in their pair-fed controls receiving vitamin B(12). A group of four animals that were maintained throughout the experiment at pasture was also studied. 2. After 34-40 weeks on the cobalt-deficient diet urinary excretion of formiminoglutamate by four deficient animals was about 3.2mmol/day and this was not significantly decreased by injection of three of them with about 4.5mug of [2-(14)C]folate/kg body weight per day for 5 days. Three days after the last injection retention of [2-(14)C]folate by the livers of the deficient animals (5.5% of the dose) was lower than that of their pair-fed controls (26% of the dose) but there was no evidence of net retention of injected folate in the livers of either group. Urinary excretion of (14)C indicated that renal clearance of folate may have been impaired in very severe vitamin B(12) deficiency. 3. As estimated by microbiological assays total folates in the livers of animals at pasture (12.9mug/g) included about 24% of 5-methyltetrahydrofolate as compared with about 72% of a total of 12.5mug/g in three further ewes fed on a stock diet of wheaten hay-chaff and lucerne-chaff. Liver folates of vitamin B(12)-deficient animals (0.5mug/g) included about 88% of 5-methyltetrahydrofolate as compared with about 51% of a total of 5.2mug/g in pair-fed animals treated with vitamin B(12). 4. Chromatography of liver folates of the pair-fed animals permitted quantitative estimates of the pteroylglutamates present. The results showed that the vitamin B(12)-deficient livers were more severely depleted of tetrahydrofolates and formyltetrahydrofolates than of methyltetrahydrofolates and that as the deficiency developed they were more severely depleted of the higher polyglutamates than of the monoglutamate within each of these classes. Results from animals injected with [2-(14)C]folate indicated an impairment of the exchange between pteroylmonoglutamates and pteroylpolyglutamates in the livers of deficient animals. 5. In vitamin B(12)-deficient animals with food intakes below 200g/day some of the liver folates were not completely reduced and some degradation of pteroylpolyglutamates was detected. The latter condition may have been associated with fatty liver. 6. The results are discussed in relation to current theories of vitamin B(12)-folate interactions.
Animals↗
Folic acid metabolism in vitamin B12-deficient sheep. Effects of injected methionine on liver constituents associated with folate metabolism.
1. The effects of injected l-methionine (2g every second day for 28 days) on liver folates and other constituents of liver associated with folate metabolism were studied in vitamin B(12)-deficient ewes and their pair-fed controls receiving vitamin B(12). The dose rate of methionine used was sufficient to restore almost to normal the elevated excretion in the urine of formiminoglutamate in the deficient animals. 2. Liver folates active for Lactobacillus casei, Streptococcus faecalis R and Pediococcus cerevisiae were severely depressed in deficient livers and were partly restored by methionine. Analysis of the folates after ion-exchange chromatography showed that the major effect of methionine was to increase the concentrations of tetrahydrofolates and formyltetrahydrofolates. Methyltetrahydrofolates were also increased, but there was no effect of methionine on the small amounts of incompletely reduced folates present in deficient livers. The folates present were predominantly penta-, hexa- and hepta-glutamates whether or not animals received vitamin B(12) or methionine. 3. Concentrations of ATP, NAD(+), NADH and NADPH were lower in freeze-clamped liver from vitamin B(12)-deficient sheep than in liver from pair-fed, vitamin B(12)-treated sheep. These changes were not affected by methionine which was also without effect on the elevated K(+)/Na(+) ratios found in deficient livers. 4. The livers of vitamin B(12)-deficient animals contained lower concentrations of choline and higher concentrations of lipid than their pair-fed controls. These effects were reversed by methionine.
Adenosine Triphosphate↗
On the evolution of arginases and related enzymes.
Sequence analysis of the arginase/agmatine ureohydrolase family, important enzymes in arginine/agmatine metabolism and the urea cycle, reveals the similarity of arginases to formiminoglutamate hydrolase (hutG) in Klebsiella aerogenes and to a previously unidentified open reading frame adjacent to the HMf locus of the archaebacterium Methanothermus fervidus. The gene structure and distribution of these homologous proteins across primary kingdoms suggest that this family is another example of a primordial enzyme possibly present in the universal common ancestor and that can be used as phylogenetic marker.
Amino Acid Sequence↗
Crystallization and preliminary X-ray analysis of the formiminotransferase domain from the bifunctional enzyme formiminotransferase-cyclodeaminase.
Formiminotransferase-cyclodeaminase (E.C. 2.1.2.5-E.C. 4.3.1.4) is a bifunctional enzyme involved in the histidine-degradation pathway which exhibits specificity for polyglutamylated folate substrates. The first function of the enzyme transfers the formimino group of formiminoglutamate to the N5 position of tetrahydrofolate, while the second function catalyses the cyclodeamination of the formimino group, yielding N5,10-methenyl-tetrahydrofolate, with efficient channeling of the intermediate between these activities. Initial studies have shown that the enzyme consists of eight identical subunits of 62 kDa each, arranged as a circular tetramer of dimers. It is this formation which results in two different dimeric interfaces, which are necessary for the two different activities. The identical subunits have been shown to consist of two domains, each of which can be obtained as dimers. The formiminotransferase domain has been crystallized in the presence of the substrate analogue folinic acid. The crystals belong to space group P212121, with unit-cell dimensions a = 64.4, b = 103.7, c = 122.3 A. Both a native data set and a mercurial derivative data set have been collected to 2.8 A resolution.
Ammonia-Lyases↗
The control of the enzymes degrading histidine and related imidazolyl derivates in Pseudomonas testosteroni.
1. The induction of the enzymes for the degradation of l-histidine, imidazolylpropionate and imidazolyl-l-lactate in Pseudomonas testosteroni was investigated. 2. The activities of histidine ammonia-lyase, histidine-2-oxoglutarate aminotransferase and urocanase are consistent with these enzymes being subject to co-ordinate control under most growth conditions. However, a further regulatory mechanism may be superimposed for histidase alone under conditions where degradation of histidine must take place for growth to occur. 3. Experiments with a urocanase(-) mutant show that urocanate is an inducer for the enzymes given above and also for N-formiminoglutamate hydrolyase and N-formylglutamate hydrolase. 4. N-Formiminoglutamate hydrolase and N-formylglutamate hydrolase are also induced by their substrates, and it is suggested that these two enzymes may be different gene products from those expressed in the presence of urocanate. 5. Induction of the enzyme system for the oxidation of imidazolylpropionate is dependent on exposure of cells to this compound.
Biological Transport↗
Organization and multiple regulation of histidine utilization genes in Pseudomonas putida.
The arrangement of the histidine utilization (hut) genes in Pseudomonas putida was established by examining the structure of a DNA segment that had been cloned into Escherichia coli via a cosmid vector. Southern blot analysis revealed that the restriction patterns of the hut genes cloned into E. coli and present in the P. putida genome were identical, indicating that no detectable DNA rearrangement took place during the cloning. Expression of the hut genes from a series of overlapping clones indicated the gene order to be hutG-hutI-hutH-hutU-hutC-hutF. The transcription directions of the different hut genes were determined by cloning the genes under control of the lambda pL promoter. This showed that hutF, encoding formiminoglutamate hydrolase, was transcribed in a direction opposite to that of the other genes. Inactivation of the cloned hut genes by Tn1000 insertion revealed that the hut genes were divided into three major transcriptional units (hutF, hutC [the repressor gene], and hut UHIG), but hutG may also be independently transcribed. When cloned individually with hutC on the same vector, hutF and hutU (which encodes urocanase) expression was induced by urocanate, indicating that these two genes each possess an operator-promoter element. Tn1000 insertions (in the cloned genes) or Tn5 insertions (in the P. putida genome) affecting the hutI or hutH gene only partially eliminated hutG expression. Furthermore, hutG, which specifies N-formylglutamate amidohydrolase, was regulated by the hutC product when the two genes were cloned on the same vector and expressed in E. coli. Therefore, hutG can be expressed independently from its own promoter, in keeping with earlier observations that N-formylglutamate amidohydrolase synthesis is not coordinated with that of urocanase and histidase and can be induced by N-formylglutamate or urocanate.
Cloning, Molecular↗