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Y Deyashiki

Publications and source records attributed to Y Deyashiki.

At least 19 recordsLinked to original sources
PubMed1999

Genetic mechanisms of age regulation of human blood coagulation factor IX.

Blood coagulation capacity increases with age in healthy individuals. Through extensive longitudinal analyses of human factor IX gene expression in transgenic mice, two essential age-regulatory elements, AE5' and AE3', have been identified. These elements are required and together are sufficient for normal age regulation of factor IX expression. AE5', a PEA-3 related element present in the 5' upstream region of the gene encoding factor IX, is responsible for age-stable expression of the gene. AE3', in the middle of the 3' untranslated region, is responsible for age-associated elevation in messenger RNA levels. In a concerted manner, AE5' and AE3' recapitulate natural patterns of the advancing age-associated increase in factor IX gene expression.

3' Untranslated Regions↗
PubMed1999

Complete nucleotide sequence, origin of isoform and functional characterization of the mouse hepsin gene.

Hepsin, a type-II membrane-associated serine protease, has been implicated in cell growth and development as well as possible initiation of blood coagulation. Here, we report on the complete nucleotide sequence, functional characterization of key structural features and the promoter of the mouse hepsin gene. The gene has a size of approximately 17 kb, and is composed of 12, 13, or 14 exons depending on alternative intron splicings - one in the 5'-UTR and the other two in the second intron. The latter two, which occur in approximately half of the hepsin transcripts, generate a hepsin mRNA species with an extra exon, which is responsible for producing a hepsin isoform with a unique 20-residue sequence inserted in the cytoplasmic portion of hepsin. Most hepsin transcripts have the 5'-UTR intron spliced, and its splicing can occur independently of the other alternative splicings. The transcriptional initiation site was determined to be 636 bp upstream of the first ATG site in a cytidine-rich region. The 5'-flanking region of hepsin up to nucleotide 274 showed a substantial promoter activity in HepG2 cells, with its expression activity sevenfold higher in the presence of the 5'-UTR intron sequence in comparison to that without the intron sequence. The basal promoter region contains potential binding sites for several transcription factors including SP1, AP2, C/EBP, LF-A1, and E box, which may be responsible for ubiquitous, but liver- and kidney-preferred tissue expression of the hepsin gene.

Alternative Splicing↗
PubMed1998

Roles of the C-terminal domains of human dihydrodiol dehydrogenase isoforms in the binding of substrates and modulators: probing with chimaeric enzymes.

Human liver dihydrodiol dehydrogenase (DD; EC 1.3.1.20) exists in isoforms (DD1, DD2 and DD4) composed of 323 amino acids. DD1 and DD2 share 98% amino acid sequence identity, but show lower identities (approx. 83%) with DD4, in which a marked difference is seen in the C-terminal ten amino acids. DD4 exhibits unique catalytic properties, such as the ability to oxidize both (R)- and (S)-alicyclic alcohols equally, high dehydrogenase activity for bile acids, potent inhibition by steroidal anti-inflammatory drugs and activation by sulphobromophthalein and clofibric acid derivatives. In this study, we have prepared chimaeric enzymes, in which we exchanged the C-terminal 39 residues between the two enzymes. Compared with DD1, CDD1-4 (DD1 with the C-terminal sequence of DD4) had increased kcat/Km values for 3alpha-hydroxy-5beta-androstanes and bile acids of 3-9-fold and decreased values for the other substrates by 5-100-fold. It also became highly sensitive to DD4 inhibitors such as phenolphthalein and hexoestrol. Another chimaeric enzyme, CDD4-1 (DD4 with the C-terminal sequence of DD1), showed the same (S)-stereospecificity for the alicyclic alcohols as DD1, had decreased kcat/Km values for bile acids with 7beta- or 12alpha-hydroxy groups by more than 120-fold and was resistant to inhibition by betamethasone. In addition, the activation effects of sulphobromophthalein and bezafibrate decreased or disappeared for CDD4-1. The recombinant DD4 with the His314-->Pro (the corresponding residue of DD1) mutation showed intermediate changes in the properties between those of wild-type DD4 and CDD4-1. The results indicate that the binding of substrates, inhibitors and activators to the enzymes is controlled by residues in their C-terminal domains; multiple residues co-ordinately act as determinants for substrate specificity and inhibitor sensitivity.

Amino Acid Sequence↗
PubMed1998

Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA.

Human liver contains three isoforms (DD1, DD2 and DD4) of dihydrodiol dehydrogenase with 20alpha- or 3alpha-hydroxysteroid dehydrogenase activity; the dehydrogenases belong to the aldo-oxo reductase (AKR) superfamily. cDNA species encoding DD1 and DD4 have been identified. However, four cDNA species with more than 99% sequence identity have been cloned and are compatible with a partial amino acid sequence of DD2. In this study we have isolated a cDNA clone encoding DD2, which was confirmed by comparison of the properties of the recombinant and hepatic enzymes. This cDNA showed differences of one, two, four and five nucleotides from the previously reported four cDNA species for a dehydrogenase of human colon carcinoma HT29 cells, human prostatic 3alpha-hydroxysteroid dehydrogenase, a human liver 3alpha-hydroxysteroid dehydrogenase-like protein and chlordecone reductase-like protein respectively. Expression of mRNA species for the five similar cDNA species in 20 liver samples and 10 other different tissue samples was examined by reverse transcriptase-mediated PCR with specific primers followed by diagnostic restriction with endonucleases. All the tissues expressed only one mRNA species corresponding to the newly identified cDNA for DD2: mRNA transcripts corresponding to the other cDNA species were not detected. We suggest that the new cDNA is derived from the principal gene for DD2, which has been named AKR1C2 by a new nomenclature for the AKR superfamily. It is possible that some of the other cDNA species previously reported are rare allelic variants of this gene.

Base Sequence↗
PubMed1998

Identification of a principal mRNA species for human 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high prostaglandin D2 11-ketoreductase activity.

Human 3alpha-hydroxysteroid dehydrogenase exists in four isoforms, which belong to the aldo-keto reductase (AKR) superfamily and are named AKR1C1-AKR1C4. The properties of AKR1C3 have not been fully characterized compared to the other isoforms. In addition, a cDNA that shows more than 99% homology with AKR1C3 cDNA has been cloned from human myeloblasts. We have here expressed and purified a recombinant enzyme (designated as DBDH) from this cDNA. DBDH oxidized xenobiotic alicyclic alcohols and 3alpha- or 17beta-hydroxy-5beta-androstanes, and catalyzed the reversible conversion between prostaglandin D2 and 9alpha,11beta-prostaglandin F2 more efficiently than that of 3alpha- or 17beta-hydroxysteroids:the respective Km values were 0.6 and 6.8 microM, and kcat/Km values were about 1,000 min-1.mM-1. Anti-inflammatory drugs highly inhibited the enzyme. The recombinant AKR1C3 prepared by site-directed mutagenesis of DBDH also showed the same properties as the wild-type DBDH. Analyses of expression of mRNAs for DBDH and AKR1C3 by reverse transcription-PCR indicated that only one mRNA species for DBDH is expressed in 33 human specimens of liver, kidney, lung, brain, heart, spleen, adrenal gland, small intestine, placenta, prostate, and testis. These results suggest that AKR1C3 acts as prostaglandin D2 11-ketoreductase, and that its principal gene in the human has a coding region represented by DBDH cDNA.

3-Hydroxysteroid Dehydrogenases↗
PubMed1998

Activation of human liver 3alpha-hydroxysteroid dehydrogenase by clofibrate derivatives.

The NADP+-dependent dehydrogenase activity of a predominant isoenzyme of human liver 3alpha-hydroxysteroid dehydrogenase was activated by antihyperlipidemic drugs, such as bezafibrate and clinofibrate, and by clofibric acid and fenofibric acid (active metabolites of clofibrate and fenofibrate, respectively). The optimal pH of the activation by the drugs was about 7.5, and the concentrations giving maximum stimulation (1.8- to 2.4-fold) were 100, 50, 400 and 50 microM for bezafibrate, clinofibrate, clofibric acid and fenofibric acid, respectively. Clofibrate and fenofibrate acted as weak inhibitors, and the clofibric acid derivatives that lack the chloro group, methyl group on the alpha-carbon or carboxyl group greatly decreased the stimulatory effects. The activation by the drugs increased both Km and kcat (turnover number) values for the coenzyme and substrates. Kinetic analysis with respect to NADP+ showed that bezafibrate, clinofibrate, clofibric acid and fenofibric acid were nonessential activators showing dissociation constants of 32, 6, 103 and 11 microM, respectively. The combined activators experiments with one of the above drugs and sulfobromophthalein, a known activator specific for this enzyme, and comparison of their effects on the activities of mutant enzymes (with Met replacing Lys-270 or Arg-276) indicated that sulfobromophthalein and the drugs bind to an identical site on the enzyme. These results suggest that the long-term therapy with the antihyperlipidemic drugs influences the metabolism of steroid hormones, bile acids and several ketone-containing drugs mediated by the enzyme.

Alcohol Oxidoreductases↗
PubMed1997

Identification of amino acid residues responsible for differences in substrate specificity and inhibitor sensitivity between two human liver dihydrodiol dehydrogenase isoenzymes by site-directed mutagenesis.

Human liver dihydrodiol dehydrogenase isoenzymes (DD1 and DD2), in which only seven amino acid residues are substituted, differ remarkably in specificity for steroidal substrates and inhibitor sensitivity: DD1 shows 20alpha-hydroxysteroid dehydrogenase activity and sensitivity to 1,10-phenanthroline, whereas DD2 oxidizes 3alpha-hydroxysteroids and is highly inhibited by bile acids. In the present study we performed site-directed mutagenesis of the seven residues (Thr-38, Arg-47, Leu-54, Cys-87, Val-151, Arg-170 and Gln-172) of DD1 to the corresponding residues (Val, His, Val, Ser, Met, His and Leu respectively) of DD2. Of the seven mutations, only the replacement of Leu-54 with Val produced an enzyme that had almost the same properties as DD2. No significant changes were observed in the other mutant enzymes. An additional site-directed mutagenesis of Tyr-55 of DD1 to Phe yielded an inactive protein, suggesting the catalytically important role of this residue. Thus a residue at a position before the catalytic Tyr residue might play a key role in determining the orientation of the substrates and inhibitors.

Amino Acids↗
PubMed1997

Involvement of two basic residues (Lys-270 and Arg-276) of human liver 3 alpha-hydroxysteroid dehydrogenase in NADP(H) binding and activation by sulphobromophthalein: site-directed mutagenesis and kinetic analysis.

A human liver 3 alpha-hydroxysteroid dehydrogenase isoenzyme, a member of the aldo-keto reductase family, shows a marked preference for NADP(H) over NAD(H), and is activated by sulphobromophthalein, which increases the Km values for both NADP(H) and substrates. Here we report kinetic alterations in binding of the coenzymes and the activator to the enzyme caused by site-directed mutagenesis of Lys-270 and Arg-276, which are strictly conserved among the aldo-keto reductase family of enzymes. The mutated enzymes, K270M and R276M, showed increases in the Km for NADP+ of 22- and 290-fold respectively; the Km for alcohol substrate and the kca1 of the NADP(-)-linked reaction were also elevated, by 9- and 5-fold respectively. No kinetic constant of the NAD(+)-linked reaction was altered by more than 3-fold. Calculation of the free-energy changes showed that the 2'-phosphate group of NADP+ contributes 16.3 kJ/mol (3.9 kcal/mol) of binding energy to its interaction with the wildtype enzyme, and the mutagenesis to K270M and R276M destabilized the binding energy of NADP+ by 6.3 and 13.0 kJ/mol (1.5 and 3.1 kcal/mol) respectively. In addition, the mutations attenuated enzyme activation by sulphobromophthalein, which bound to the mutant enzymes as an inhibitor. The inhibition for the R276M mutant was competitive with respect to NADP+ and non-competitive with respect to the substrate, whereas that for the K270M mutant was mixed-type, showing activation at coenzyme concentrations greater than 20 x Km. These results suggest that the two basic residues in the 3 alpha-hydroxysteroid dehydrogenase isoenzyme play crucial roles in binding both the negatively charged 2'-phosphate group of NADP+ and the sulphonic groups of sulphobromophthalein.

3-Hydroxysteroid Dehydrogenases↗
PubMed1997

[A sensitive fluorometric assay for dihydrodiol dehydrogenase].

Dihydrodiol dehydrogenase (DD) oxidizes naphthalene dihydrodiol to 1,2-dihydroxynaphthalene, which is immediately autoxidized to 1,2-naphthoquinone. Here we established a fluorometric assay for the enzyme, which is based on the conversion of 1,2-naphthoquinone to fluorescent compounds by reacting with ethylenediamine. The formed fluorescent compounds were synthetically identified as 6-(2-aminoethylamino)benzo[f]quinoxaline and 2,6- or 3,6-bis(2-aminoethylamino)benzo[f]quinoxaline, which showed the same fluorescence at 550 nm at an excitation wavelength of 420 nm. This method provides a 9000-fold increase in sensitivity over a currently available assay which measures the change in the absorbance of a cofactor, NADPH. Since this simple and sensitive method allowed many samples to be assayed simultaneously, we applied it to the analysis of multiple forms of DD, separated by an anion-exchange chromatography, from six human liver specimens.

Ethylenediamines↗
PubMed1996

Aldose reductase is a major reductase for isocaproaldehyde, a product of side-chain cleavage of cholesterol, in human and animal adrenal glands.

Isocaproaldehyde (4-methylpentanal) is a product of the side-chain cleavage of cholesterol, the first step of steroid biosynthesis. Here, we report the characterization of enzymes responsible for the oxidoreduction of isocaproaldehyde in human, monkey, dog, and rabbit adrenal glands. NADPH-linked isocaproaldehyde reductase activity in the adrenal extracts of the four species was much higher than the NADH-linked reductase and NAD(P)(+)-linked dehydrogenase activities and was potently inhibited by aldose reductase inhibitors. The major species of isocaproaldehyde reductase purified from the four mammalian adrenal glands were biochemically identical with aldose reductase, and exhibited Km values of 1 microM. The contents of aldose reductase in adrenal glands of the four mammals were relatively high, and its localization in canine adrenal cortex was immunohistochemically demonstrated. In addition, the purified aldose reductases and recombinant human aldose reductase reduced other alkanals and alkenals at low Km values of 2-61 microM, and their catalytic efficiencies were higher than that of human aldehyde reductase. Thus, aldose reductase acts not only as a major reductase for isocaproaldehyde formed from steroidogenesis but also as a scavenger of aldehydes derived from lipid peroxidation in mammalian adrenal glands.

Adrenal Glands↗
PubMed1996

Crystal structure of the ternary complex of mouse lung carbonyl reductase at 1.8 A resolution: the structural origin of coenzyme specificity in the short-chain dehydrogenase/reductase family.

BACKGROUND: Mouse lung carbonyl reductase (MLCR) is a member of the short-chain dehydrogenase/reductase (SDR) family. Although it uses both NADPH and NADH as coenzymes, the structural basis of its strong preference for NADPH is unknown. RESULTS: The crystal structure of the ternary complex of MLCR (with NADPH and 2-propanol) has been determined at 1.8 A resolution. This is the first three-dimensional structure of a carbonyl reductase, and MLCR is the first member of the SDR family to be solved in complex with NADPH (rather than NADH). Comparison of the MLCR ternary complex with three structures reported previously for enzymes of the SDR family (all crystallized as complexes with NADH) reveals a pair of basic residues (Lys17 and Arg39) making strong electrostatic interactions with the 2'-phosphate group of NADPH. This pair of residues is well conserved among the NADPH-preferring enzymes of the SDR family, but not among the NADH-preferring enzymes. In the latter, an aspartate side chain occupies the position of the two basic side chains. The aspartate residue, which would come into unacceptably close contact with the 2'-phosphate group of the adenosine moiety of NADPH, is replaced by a threonine or alanine in the primary sequences of NADPH-preferring enzymes of the SDR family. CONCLUSIONS: The cofactor preferences exhibited by the enzymes of the SDR family are mainly determined by the electrostatic environment surrounding the 2'-hydroxyl (or phosphate) group of the adenosine ribose moiety of NADH (or NADPH). Thus, positively charged and negatively charged environments correlate with preference for NADPH and NADH respectively.

1-Propanol↗
PubMed1996

Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells.

We previously isolated three monomeric dihydrodiol dehydrogenases, DD1, DD2 and DD4, from human liver, and cloned a cDNA (C9) thought to encode DD2, which is identical with those for human bile-acid-binding protein and an oxidoreductase of human colon carcinoma HT29 cells. In the present study we have provided evidence that the C9 cDNA clone encodes DD1, not DD2. A recombinant enzyme expressed from the cDNA in a bacterial system was purified, and its catalytic properties, bile-acid-binding ability and primary sequence were compared with those of the hepatic dihydrodiol dehydrogenases. The results show that DD1 encoded by C9 possesses prostaglandin F synthase activity but low affinity for lithocholic acid, whereas DD2, showing differences of six amino acid residues from the DD1 sequence, exhibited high-affinity binding for the bile acid. Refined relationship between dihydrodiol dehydrogenases and their related proteins of human tissues is proposed.

Amino Acid Sequence↗
PubMed1996

Activation of human liver 3 alpha-hydroxysteroid dehydrogenase by sulphobromophthalein.

Human liver contains at least two isoenzymes (DD2 and DD4) of 3 alpha-hydroxysteroid/dihydrodiol dehydrogenase. The NADP(H)-linked oxidoreductase activities of DD4 were activated more than 4-fold by sulphobromophthalein at concentrations above 20 microM and under physiological pH conditions. Sulphobromophthalein did not stimulate the activities of DD2 and human liver aldehyde reductase, which are functionally and/or structurally related to DD4. No stimulatory effect on the activity of DD4 was observed with other organic anions such as Indocyanine Green, haematin and Rose Bengal. The binding of sulphobromophthalein to DD4 was instantaneous and reversible, and was detected by fluorescence and ultrafiltration assays. The activation by sulphobromophthalein decreased the activation energy in the dehydrogenation reaction for the enzyme, and increased both kcat, and Km values for the coenzymes and substrates. Kinetic analyses with respect to concentrations of NADP+ and (S)-(+)-indan-1-ol indicated that sulphobromophthalein was a non-essential activator of mixed type showing a dissociation constant of 2.6 microM. Thus, the human 3 alpha-hydroxysteroid dehydrogenase isoenzyme has a binding site specific to sulphobromophthalein, and the hepatic metabolism mediated by this isoenzyme may be influenced when this drug is administered.

3-Hydroxysteroid Dehydrogenases↗
PubMed1996

Involvement of two basic residues (Lys-17 and Arg-39) of mouse lung carbonyl reductase in NADP(H)-binding and fatty acid activation: site-directed mutagenesis and kinetic analyses.

Mouse lung carbonyl reductase, a member of the short-chain dehydrogenase/reductase (SDR) family, shows a strong coenzyme preference for NADP(H) over NAD(H), and is uniquely activated by fatty acids. Previous chemical modification and X-ray crystallography studies show that interactions responsible for the coenzyme specificity include salt linkages between the 2'-phosphate of NADPH and side-chains of Lys-17 and Arg-39 of the enzyme. Although Arg-39 is highly conserved in NADP(H)-dependent enzymes of the SDR family, Lys-17 is substituted with Arg in about half of the NADP(H)-dependent enzymes. The present study shows that mutations of Lys-17 to His (K17H) or Ser (K17S) and of Arg-39 to Ala (R39A) bring about decreases (from 5 to 90-fold) of the affinities for NADP(H), but minor changes in the affinity for NAD+. The binding energy arising from the mutations on the binding of the 2'-phosphate of NADP+ was decreased by 38-66% from the value of 4.8 kcal/mol calculated for the wild-type enzyme. In contrast, the mutation of Lys-17 to Arg (K17R) had little effect on the kinetic or thermodynamic properties. The activation by fatty acids was completely attenuated by the mutations of K17H and K17S, but not by K17R or R39A. These results indicate that the 2'-phosphate group of NADP(H) is recognized by both Lys-17 and Arg-39, of which Lys-17 is a component of the binding site for the activator, probably interacting with the negatively charged carboxylate group of fatty acids, and also suggest that the existence of a positively charged residue (either Lys or Arg) at position 17 is required for both NADP(H) specificity of the SDR family enzymes and fatty acid activation of the pulmonary carbonyl reductase.

Alcohol Oxidoreductases↗
PubMed1995

Reduction of drug ketones by dihydrodiol dehydrogenases, carbonyl reductase and aldehyde reductase of human liver.

In this study, we compared the enzymatic reduction of 10 drugs with a ketone group by homogeneous carbonyl reductase, aldehyde reductase and three dihydrodiol dehydrogenases of human liver cytosol. At least one and in some cases all of the three dihydrodiol dehydrogenases reduced each of the ten drugs. Among these naloxone, naltrexone, befunolol, ethacrynic acid and ketoprofen were substrates specific for the dehydrogenases. The other drugs--haloperidol, metyrapone, loxoprofen, daunorubicin and acetohexamide--were highly reduced by carbonyl reductase and/or aldehyde reductase. The dihydrodiol dehydrogenases also showed lower Km values for haloperidol and loxoprofen than did carbonyl reductase. The results indicate that the three dihydrodiol dehydrogenases, as well as the two reductases, are implicated in the reduction of ketone-containing drugs in human liver cytosol.

Alcohol Oxidoreductases↗
PubMed1995

Molecular cloning and characterization of mouse estradiol 17 beta-dehydrogenase (A-specific), a member of the aldoketoreductase family.

Several mammalian livers contain monomeric 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) with A-stereospecificity in hydrogen transfer, which differs from the B-specific dimeric enzyme of human placenta in its ability to catalyze the oxidoreduction of xenobiotic trans-dihydrodiols of aromatic hydrocarbons and carbonyl compounds. Here, we report the isolation and characterization of a mouse cDNA clone encoding monomeric 17 beta-HSD of the liver. This clone had an entire coding region for a protein of 323 amino acid residues with a molecular weight of 37,055. The deduced sequence of the protein aligned with a high degree of identity with rat and rabbit 20 alpha-HSDs, rat and human 3 alpha-HSD/dihydrodiol dehydrogenases, and bovine prostaglandin F synthase, which are members of the aldoketoreductase family, but was distinct from human 17 beta-HSD and carbonyl reductase, members of the short chain dehydrogenases. The expression of the cDNA in Escherichia coli resulted in synthesis of a protein that was active toward androgens, estrogens, and xenobiotic substrates. The recombinant and mouse liver 17 beta-HSDs also exhibited low 20 alpha-HSD activity toward progestins, which is similar to bifunctional activity of human placental 17 beta-HSD. Therefore, the mouse enzyme was given the designation of estradiol 17 beta-dehydrogenase (A-specific). Northern analysis of mouse tissues revealed the existence of a single 1.7-kilobase 17 beta-HSD mRNA species in the liver, kidney, testis, and stomach. The liver mRNA content was considerably more abundant than those found in the other tissues, as 17 beta-HSD protein was mainly detected in the liver by Western analysis.

Amino Acid Sequence↗
PubMed1995

Cloning, expression and tissue distribution of mouse tetrameric carbonyl reductase. Identity with an adipocyte 27-kDa protein.

We previously cloned a cDNA for pig lung tetrameric carbonyl reductase which shows significant similarity to a putative 27-kDa protein predicted from the cDNA for murine adipocyte RNA which had been increased in its differentiation [Nakanishi, M., Deyashiki, Y., Nakayama, T., Sato, K. & Hara, A. (1993) Biochem. Biophys. Res. Commun. 194, 1311-1316]. In this investigation, we isolated and sequenced a full-length cDNA for the tetrameric enzyme from a mouse lung cDNA library. It consisted of 984 bp and coded for a protein of 244 amino acid residues, of which 202 residues were identified by protein sequencing. The expression of the cDNA in Escherichia coli resulted in synthesis of a protein structurally and functionally similar to the enzyme purified from mouse lung. The nucleotide sequence of the cDNA was virtually identical to that of the cDNA for the adipocyte 27-kDa protein. Although Northern-blot analysis of mouse tissues showed that enzyme mRNA to be 1.1 kb only in lung, low expression of the mRNA in all the extrapulmonary tissues, including adipose tissue, was demonstrated by a reverse-transcription PCR method. Western-blot analysis also indicated the presence of the enzyme in the adipose tissue. This is the first report on an identification of the putative gene product of adipocytes as tetrameric carbonyl reductase, the expression of which is tissue-specifically regulated.

Adipocytes↗