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PubMed2004

Substrate specificity of native and mutated cytochrome P450 (CYP102A3) from Bacillus subtilis.

Within the Bacillus subtilis genome sequencing project, two monooxygenases (CYP102A2 and CYP102A3) were discovered which revealed a similarity of 76% to the well-known cytochrome P450 BM-3 (CYP102A1) of Bacillus megaterium. All enzymes are natural fusion proteins consisting of a heme domain and a reductase domain. We here report the cloning, expression and characterization of B. subtilis enzyme CYP102A3. The substrate specificity of this enzyme is similar to that of B. megaterium CYP102A1, which hydroxylates medium-chain fatty acids in subterminal positions. A double mutant was prepared that hydroxylates a number of other substrates, which do not bear any resemblance to the natural substrate of this enzyme family.

Bacillus subtilis↗
PubMed2001

Structures of two natural product methyltransferases reveal the basis for substrate specificity in plant O-methyltransferases.

Chalcone O-methyltransferase (ChOMT) and isoflavone O-methyltransferase (IOMT) are S-adenosyl-l-methionine (SAM) dependent plant natural product methyltransferases involved in secondary metabolism in Medicago sativa (alfalfa). Here we report the crystal structure of ChOMT in complex with the product S-adenosyl-l-homocysteine and the substrate isoliquiritigenin (4,2',4'-trihydroxychalcone) refined to 1.8 A as well as the crystal structure of IOMT in complex with the products S-adenosyl-l-homocysteine and isoformononetin (4'-hydroxy-7-methoxyisoflavone) refined to 1.4 A. These two OMTs constitute the first plant methyltransferases to be structurally characterized and reveal a novel oligomerization domain and the molecular determinants for substrate selection. As such, this work provides a structural basis for understanding the substrate specificity of the diverse family of plant OMTs and facilitates the engineering of novel activities in this extensive class of natural product biosynthetic enzymes.

Amino Acid Sequence↗
PubMed2001

Evaluation of the substrate specificity of human mast cell tryptase beta I and demonstration of its importance in bacterial infections of the lung.

Human pulmonary mast cells (MCs) express tryptases alpha and beta I, and both granule serine proteases are exocytosed during inflammatory events. Recombinant forms of these tryptases were generated for the first time to evaluate their substrate specificities at the biochemical level and then to address their physiologic roles in pulmonary inflammation. Analysis of a tryptase-specific, phage display peptide library revealed that tryptase beta I prefers to cleave peptides with 1 or more Pro residues flanked by 2 positively charged residues. Although recombinant tryptase beta I was unable to activate cultured cells that express different types of protease-activated receptors, the numbers of neutrophils increased >100-fold when enzymatically active tryptase beta I was instilled into the lungs of mice. In contrast, the numbers of lymphocytes and eosinophils in the airspaces did not change significantly. More important, the tryptase beta I-treated mice exhibited normal airway responsiveness. Neutrophils did not extravasate into the lungs of tryptase alpha-treated mice. Thus, this is the first study to demonstrate that the two nearly identical human MC tryptases are functionally distinct in vivo. When MC-deficient W/W(v) mice were given enzymatically active tryptase beta I or its inactive zymogen before pulmonary infection with Klebsiella pneumoniae, tryptase beta I-treated W/W(v) mice had fewer viable bacteria in their lungs relative to zymogen-treated W/W(v) mice. Because neutrophils are required to combat bacterial infections, human tryptase beta I plays a critical role in the antibacterial host defenses of the lung by recruiting neutrophils in a manner that does not alter airway reactivity.

Amino Acid Sequence↗
PubMed2007

High-throughput substrate specificity studies of sialidases by using chemoenzymatically synthesized sialoside libraries.

Sialidases, or neuraminidases, are enzymes that cleave terminal sialic acid (Sia) residues from complex sialic acid-containing structures. They have been found in many animals and microorganisms and are important in various physiological and pathological processes. In order to understand the biological significance of diverse sialidases, it is important to study in detail the structural determinants of their natural substrates. Here, we report the synthesis of sialoside libraries containing para-nitrophenol-tagged sialosides with different naturally occurring sialic acid forms, different sialyl linkages, and different penultimate monosaccharides using a highly efficient one-pot three-enzyme chemoenzymatic approach. By using these compounds in a 96-well plate-based colorimetric high-throughput screening platform, the diversity of substrate preference is shown for seven bacterial sialidases. The sialoside libraries and the screening method are convenient tools for unravelling the substrate specificity and the biological function of sialidases.

Bacterial Proteins↗
PubMed1992

Alpha-isoenzyme of alcohol dehydrogenase from monkey liver. Cloning, expression, mechanism, coenzyme, and substrate specificity.

The cDNA for the alpha-isoenzyme from rhesus monkey (Macaca mulatta) liver was cloned and expressed in yeast. The alpha-isoenzymes of human and monkey liver alcohol dehydrogenase differ from the other human and horse liver enzymes in having Met57, Ala93, and Val116 instead of Leu57, Phe93, and Leu116 in the substrate binding pocket and Gly47 instead of Arg47 near the pyrophosphate moiety of the coenzyme. The effects of these differences on the kinetic mechanism, substrate specificity, and coenzyme binding were studied with the purified, recombinant monkey alpha-isoenzyme (MmADH alpha) and mutated enzymes with Gly47 substituted with His or Arg. The mechanism appears to be random for the binding of NAD+ and ethanol and ordered for NADH and acetaldehyde, with formation of a dead-end enzyme-NADH-ethanol complex. MmADH alpha reacts 130-fold slower (V/K) with ethanol and 3-25-fold slower with 2-methyl alcohols but 20-fold faster with cyclohexanol, as compared with horse (Equus caballus) liver EE isoenzyme (EqADH). MmADH alpha is stereoselective for the R isomer of 2-butanol, whereas EqADH favors the S isomer. Both enzymes have comparable reactivity with larger primary alcohols. MmADH alpha is more reactive with secondary alcohols and has highest activity with cyclohexanol. However, it does not react with steroids such as 5 beta-androstane-17 beta-ol-3-one. Molecular modeling suggests that the differences between MmADH alpha and EqADH are a result of the substitution of Ala for Phe93 and Thr for Ser48. MmADH alpha binds NAD+ most rapidly when a group with a pK of 7.4 is unprotonated, implicating His51 in this reaction. The G47R substitution decreased the dissociation constants for NAD+ and NADH and turnover numbers only about 2-fold, whereas the G47H substitution increased dissociation constants 7-14-fold and turnover numbers 4-fold. A basic residue at position 47 is not crucial for activity, as multiple interactions determine coenzyme affinity.

Alcohol Dehydrogenase↗
PubMed1998

Substrate specificity of the human coronavirus 229E 3C-like proteinase.

Coronavirus gene expression involves proteolytic processing of the gene 1-encoded polyproteins and a key enzyme in this process is the virus-encoded 3C-like proteinase. In this study, we describe the biosynthesis of the human coronavirus 229E 3C-like proteinase in Escherichia coli and the substrate specificity of the purified protein. Using immunofluorescence microscopy, we have also investigated the subcellular localization of the 3C-like proteinase and have found a punctate, perinuclear distribution of the proteinase in virus-infected cells.

3C Viral Proteases↗
PubMed2006

Probing the substrate specificity of the dengue virus type 2 NS3 serine protease by using internally quenched fluorescent peptides.

The NS3 (dengue virus non-structural protein 3) serine protease of dengue virus is an essential component for virus maturation, thus representing an attractive target for the development of antiviral drugs directed at the inhibition of polyprotein processing. In the present study, we have investigated determinants of substrate specificity of the dengue virus NS3 protease by using internally quenched fluorogenic peptides containing Abz (o-aminobenzoic acid; synonymous to anthranilic acid) and 3-nitrotyrosine (nY) representing both native and chimaeric polyprotein cleavage site sequences. By using this combinatorial approach, we were able to describe the substrate preferences and determinants of specificity for the dengue virus NS2B(H)-NS3pro protease. Kinetic parameters (kcat/K(m)) for the hydrolysis of peptide substrates with systematic truncations at the prime and non-prime side revealed a length preference for peptides spanning the P4-P3' residues, and the peptide Abz-RRRRSAGnY-amide based on the dengue virus capsid protein processing site was discovered as a novel and efficient substrate of the NS3 protease (kcat/K(m)=11087 M(-1) x s(-1)). Thus, while having confirmed the exclusive preference of the NS3 protease for basic residues at the P1 and P2 positions, we have also shown that the presence of basic amino acids at the P3 and P4 positions is a major specificity-determining feature of the dengue virus NS3 protease. Investigation of the substrate peptide Abz-KKQRAGVLnY-amide based on the NS2B/NS3 polyprotein cleavage site demonstrated an unexpected high degree of cleavage efficiency. Chimaeric peptides with combinations of prime and non-prime sequences spanning the P4-P4' positions of all five native polyprotein cleavage sites revealed a preponderant effect of non-prime side residues on the K(m) values, whereas variations at the prime side sequences had higher impact on kcat.

Dengue Virus↗
PubMed1984

[Substrate specificity of T4 RNA-ligase. The effect of the nucleotide sequence of the minimum phosphate acceptor on the efficacy of intermolecular ligation].

The 2' (3'),5'-diphosphates of cytidine, uridine, adenosine and the trinucleoside diphosphates, such as NpCpC, NpCpU, NpUpC, NpUpU and ApNpC (where N = U, C, A, G), were used to study the substrate specificity of the T4 RNA ligase. The outcome of ligating various phosphate acceptors to a common phosphate donor was governed not only by nucleotide composition but also the nucleotide sequence of a phosphate acceptor. The effect of the changes in a single position of the phosphate acceptor on the efficiency of the intermolecular ligation cannot be defined independently of the other nucleotide residues. For four examined groups of phosphate acceptors and pCp as a donor, four different ranks were obtained (in order of decreasing reactivity): C greater than A greater than greater than U greater than G (for NpCpC); G greater than U approximately equal to A greater than C (NpCpU); A greater than U greater than C greater than G (NpUpC) and A greater than G greater than C greater than U (NpUpU). The yield of ligation products with various phosphate donors and a common phosphate acceptor significantly depends on the donor structure: pyrimidine phosphate donors are more effective than pAp, while pCp is more effective than pUp.

Base Sequence↗
PubMedDate not supplied

The catalytic effect of bovine serum albumin on the ortho rearrangement of the potential ultimate carcinogen, N-(sulfooxy)-2-(acetylamino)fluorene, generated enzymatically from N-hydroxy-2-(acetylamino)fluorene and evidence for substrate specificity of the enzymatic sulfonation of arylhydroxamic acids.

This investigation examines the catalytic effect of bovine serum albumin on the ortho rearrangement of the possible ultimate carcinogen, N-(sulfooxy)-2-(acetylamino)fluorene, generated from N-hydroxy-2-(acetylamino)fluorene by the sulfotransferase(s) in the cytosol of rat liver. With various preparations of cytosol, 55-75% of the substrate, N-hydroxy-2-(acetylamino)-fluorene, was found to rearrange to the nonmutagenic and noncarcinogenic o-(sulfooxy) esters, 1- and 3-(sulfooxy)-2-(acetylamino)fluorene, in the presence of bovine serum albumin, while less than 1% of the substrate rearranged in its absence. In presence of bovine serum albumin the cytosolic reduction of N-(sulfooxy)-2-(acetylamino)fluorene to 2-(acetylamino)fluorene decreased by 60-90% and its solvolytic degradation to 4-hydroxy-2-(acetylamino)fluorene by 80-90%. The covalent interaction of enzymatically generated N-(sulfooxy)-2-(acetylamino)fluorene with the nucleophilic acceptors, N-acetyl-L-methionine and guanosine, was lowered by greater than 90% by addition of bovine serum albumin. These measurements indicated that the albumin-catalyzed ortho rearrangement controls the rates of concurrent metabolic and degradative reactions of N-(sulfooxy)-2-(acetylamino)fluorene. The results are in agreement with previous findings of a catalytic effect of serum albumin on the ortho rearrangement of synthetic N-(sulfooxy)-2-(acetylamino)fluorene. In contrast to its catalytic effect on the formation of o-(sulfooxy) esters from N-(sulfooxy)-2-(acetylamino)fluorene, bovine serum albumin had no effect on the formation of o-(acetylamino)fluorenols. To assess the substrate specificity of bovine serum albumin, its effect on the rearrangement of N-hydroxy-2-(benzoylamino)fluorene, a carcinogenic analogue of N-hydroxy-2-(acetylamino)fluorene, was analyzed under conditions of cytosolic sulfonation.(ABSTRACT TRUNCATED AT 250 WORDS)

2-Acetylaminofluorene↗
PubMed1999

Insights into the mechanism of domain closure and substrate specificity of glutamate dehydrogenase from Clostridium symbiosum.

Comparisons of the structures of glutamate dehydrogenase (GluDH) and leucine dehydrogenase (LeuDH) have suggested that two substitutions, deep within the amino acid binding pockets of these homologous enzymes, from hydrophilic residues to hydrophobic ones are critical components of their differential substrate specificity. When one of these residues, K89, which hydrogen-bonds to the gamma-carboxyl group of the substrate l-glutamate in GluDH, was altered by site-directed mutagenesis to a leucine residue, the mutant enzyme showed increased substrate activity for methionine and norleucine but negligible activity with either glutamate or leucine. In order to understand the molecular basis of this shift in specificity we have determined the crystal structure of the K89L mutant of GluDH from Clostridium symbiosum. Analysis of the structure suggests that further subtle differences in the binding pocket prevent the mutant from using a branched hydrophobic substrate but permit the straight-chain amino acids to be used as substrates. The three-dimensional crystal structure of the GluDH from C. symbiosum has been previously determined in two distinct forms in the presence and absence of its substrate glutamate. A comparison of these two structures has revealed that the enzyme can adopt different conformations by flexing about the cleft between its two domains, providing a motion which is critical for orienting the partners involved in the hydride transfer reaction. It has previously been proposed that this conformational change is triggered by substrate binding. However, analysis of the K89L mutant shows that it adopts an almost identical conformation with that of the wild-type enzyme in the presence of substrate. Comparison of the mutant structure with both the wild-type open and closed forms has enabled us to separate conformational changes associated with substrate binding and domain motion and suggests that the domain closure may well be a property of the wild-type enzyme even in the absence of substrate.

Amino Acid Oxidoreductases↗
PubMed2002

Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4).

ADAM-TS5 (aggrecanase 2), one of two cartilage aggrecanases is a member of the ADAM protein family. Like ADAM-TS4 (aggrecanase 1) the enzyme cleaves cartilage aggrecan at the Glu(373)-Ala(374) bond, a marker of aggrecanase activity. In this study we have characterized the substrate specificity of ADAM-TS5 and compared it with that of ADAM-TS4. The recombinant human ADAM-TS5, like ADAM-TS4 cleaves aggrecan at Glu(1480)-Gly(1481), Glu(1667)-Gly(1668), Glu(1771)-Ala(1772) and Glu(1871)-Leu(1872) bonds more readily than at the Glu(373)-Ala(374) bond. In addition, ADAM-TS5 exhibited an additional site of cleavage in the region spanning residues Gly(1481) and Glu(1667), representing a unique cleavage of ADAM-TS5. ADAM-TS5 cleaved aggrecan approximately 2-fold slower than ADAM-TS4. Neither ADAM-TS5 nor ADAM-TS4 was able to cleave the extracellular matrix proteins fibronectin, thrombospondin, type I collagen, type II collagen, gelatin or general protein substrates such as casein and transferrin. Finally, the zymogen of stromelysin (MMP-3) was not activated by either ADAM-TS4 or ADAM-TS5.

ADAM Proteins↗
PubMed1991

Mechanistic studies of two amino acid racemases of broad substrate specificity from Pseudomonas striata and Aeromonas caviae.

The conversion of L-[alpha-2H]alanine in H2O and unlabeled L-alanine in 2H2O into D-alanine, under nearly irreversible conditions, with the amino acid racemase from Pseudomonas striata showed significant internal transfer of the alpha-hydrogen. This result has been interpreted as being indicative of a single base mechanism for the racemization. The relative rates of deuterium incorporation into unlabeled D- and L-methionine by the two amino acid racemases of broad substrate specificity from P. striata and Aeromonas caviae, were measured in 2H2O. The results showed a markedly different pattern, dependent upon the configuration of the initial substrate; with D-methionine as substrate deuterium is incorporated into both enantiomers at approximately the same rate, but with L-methionine as substrate deuterium is incorporated considerably faster into the D than the L enantiomer. These results argue against a single base mechanism of racemization for these enzymes and are best rationalized in terms of a double base model where only one of the bases undergoes proton (deuterium) exchange with the solvent while the amino acid is enzyme-bound. The interpretation of the earlier experiment needs to be considered in light of these results.

Aeromonas↗
PubMed2000

Alternative splicing of Drosophila calcium/calmodulin-dependent protein kinase II regulates substrate specificity and activation.

Drosophila calcium/calmodulin-dependent protein kinase II is alternatively spliced to generate multiple isoforms that vary only in a region between the calmodulin-binding domain and the association domain. This variation has been shown to modulate activation of the enzyme by calmodulin. In this study we examine the ability of seven of the Drosophila isoforms to phosphorylate purified protein substrates and to be inhibited by a substrate analog, and the response of six of the isoforms to a mutant form of calmodulin (V91G) that was isolated in a genetic screen. Significant variation in Kms for Eag, a potassium channel, and Adf-1, a transcription factor, were found. In the case of the a peptide inhibitor, AC3I, there were significant variations in Ki between isoforms. Kact for V91G calmodulin was increased for all of the isoforms. In addition, one isoform, RI, exhibited a lower Vmax when assayed with this mutant CaM. These results indicate that the variable domain of calcium/calmodulin-dependent protein kinase II is capable of altering the substrate specificity of the catalytic domain and the activation response to calmodulin.

Alternative Splicing↗
PubMed1987

Substrate specificity of DNA polymerases. I. Enzyme-catalysed incorporation of 5-'1-alkenyl)-2'-deoxyuridines into DNA.

A series of (E)-5-(1-alkenyl)-dUTPs as well as 5-vinyl-and (Z)-5-(1-propenyl)-dUTP have been synthesized to study steric requirements in DNA polymerase reactions. Experiments were carried out in E. coli DNA polymerase I Klenow fragment enzyme system. Substrates were characterized by KM and Vmax-values, initial incorporation rates as well as by total extent of incorporation of the analogues into poly(dA-dT) as a template-primer. Incorporation of the analogues could be best correlated with Vmax-values as well as the very similar initial incorporation rate values. Reactivity (Vmax/KM) showed no correlation with the extent of incorporation. 5-Vinyl-dUTP proved to be as good a substrate of the enzyme as dTTP, whereas (E)-5-(1-heptenyl)-and (E)-5-(1-octenyl)-dUTPs were very poor substrates, their incorporation was strongly limited and they also proved to be very efficient inhibitors of DNA replication, as shown by Ki-values. Substrate specificity of the Klenow enzyme can be explained by the steric hindrance of C-5 substituent, by the "orientational steric substituent effect" concept.

Alkenes↗
PubMed2002

An overview of the mechanism, substrate specificities, and structure of FMOs.

Kinetic studies carried out over the past three decades, primarily with purified pig liver flavin-containing monooxygenase (FMO1), demonstrated that the mechanism of this flavoenzyme was distinctly different from other widely studied flavin-dependent monooxygenases in that reduction of O2 by nicotinamide-adenine-dinucleotide-phosphate reduced (NADPH) occurred before the addition of the xenobiotic substrate. Compounds bearing a soft nucleophilic heteroatom show substrate activity provided they could contact the enzyme-bound 4a-hydroperoxy flavin. Structure-activity studies suggest that in addition to nucleophilicity, size and charge of potential substrates are important parameters limiting access to the enzyme-bound hydroxylating intermediate form of the enzyme. The mechanism of FMO 1, 2, 3, and 4 are similar and differences in the substrate specificities of these isoforms can be attributed almost entirely to differences in the dimensions of the cleft or channel limiting access to the 4a-hydroperoxy flavin. While this model provides a satisfactory mechanism for the FMO catalyzed oxidation of very soft nucleophiles, it does not address another very important element of the catalytic cycle. The amine nitrogen atom is not an especially soft nucleophile readily hydroxylated by peroxides or peracids. How the enzymes convert an amine substrate to a form readily attacked by the hydroperoxy flavin is presently unknown. A complete resolution of this problem will only be possible after the tertiary structures of these enzymes are solved.

Animals↗
PubMed2002

Alterations of susceptibility of Pseudomonas aeruginosa by overproduction of multidrug efflux systems, MexAB-OprM, MexCD-OprJ, and MexXY/OprM to carbapenems: substrate specificities of the efflux systems.

Overproduction of multidrug efflux systems MexAB-OprM, MexCD-OprJ, and MexXY/OprM of Pseudomonas aeruginosa caused reduction of susceptibility of the mutant, which lacked AmpC and all three systems to panipenem, meropenem, S4661 and DU6681a; meropenem, S4661 and DU6681a; and BO2727, panipenem, meropenem, S4661 and DU6681a, respectively, but not reduction of the susceptibility to imipenem and biapenem. Thus, we determined substrate specificities of these efflux systems to carbapenems.

Bacterial Outer Membrane Proteins↗
PubMed1994

Substrate specificity of Fpg protein. Recognition and cleavage of oxidatively damaged DNA.

The 8-oxoguanine-DNA glycosylase of Escherichia coli, also known as formamidopyrimidine-DNA glycosylase (Fpg protein), has N-glycosylase and AP-lyase activities. This enzyme repairs oxidative DNA damage by efficiently removing formamidopyrimidine lesions and 8-oxoguanine residues from DNA. Defined oligodeoxynucleotides containing various 8-oxopurines were used to examine the substrate specificity of Fpg protein and to establish the role of functional groups in DNA on damage recognition and catalysis. Binding affinities of Fpg protein were established for duplex oligodeoxynucleotides containing 8-oxo-2'-deoxyguanine, 8-oxo-2'-deoxyadenine, 8-oxo-2'-deoxynebularine, 8-oxo-2'-deoxyinosine, abasic sites, and a ring-open adduct of C8-aminofluorene guanine. The C8 keto group of 8-oxodG:dC presents in the major groove and is correlated with tight binding (Kd = 8.9 nM). Binding is much weaker when the C8 keto functional group is in the minor groove, as in 8-oxodG:dA (Kd = 340 nM). Km and Vmax were determined for the cleavage reaction. Specificity constants (Kcat/Km) are consistently higher for oligodeoxynucleotide duplexes containing 8-oxopurines with C6 and C8 keto groups, as in 8-oxodG:dC and 8-oxodI:dC, where Kcat/Km are 9.3 and 18 min-1 nM x 10(-3), respectively. 8-oxodN:dC lacks the C6 keto group; the specificity constant is 0.024 min-1 nM x 10(-3). Taken together, our data suggest that the C8 keto group of 8-oxodeoxyguanine and the carbonyl moiety of formamidopyrimidine enable Fpg protein to recognize and bind duplex DNA containing these modified bases. An enzyme-catalyzed reaction involving the C6 keto group of the substrate leads to removal of these lesions. A mechanism involving protonation at O-6 of 8-oxoguanine is proposed to account for the N-glycosylase activity of this enzyme.

Catalysis↗
PubMed2003

On the substrate specificity of human CYP27A1: implications for bile acid and cholestanol formation.

The mitochondrial sterol 27-hydroxylase (CYP27A1) is required for degradation of the C27-sterol side chain in bile acid biosynthesis. CYP27A1 seems, however, to have roles beyond this, as illustrated by patients with a deficient sterol 27-hydroxylase due to mutations of the CYP27A1 gene [cerebrotendinous xanthomatosis (CTX)]. These subjects have symptoms ranging from accumulation of bile alcohols and cholestanol to accelerated atherosclerosis and progressive neurologic impairment. The present work describes a detailed investigation on the substrate specificity of recombinant human CYP27A1. In accordance with some previous work with rat liver mitochondria, the activity in general increased with the polarity of the substrate. An obvious example was the finding that cholesterol was 27-hydroxylated more efficiently than cholesterol oleate but less efficiently than cholesterol sulfate. The oxysterols 24S-hydroxycholesterol and 25-hydroxycholesterol were 27-hydroxylated less efficiently than cholesterol, possibly due to steric hindrance. Surprisingly, sterols with a 3-oxo-Delta4 structure were found to be hydroxylated at a much higher rate than the corresponding sterols with a 3beta-hydroxy-Delta5 structure. The rates of hydroxylation of the sterols were: 7alpha-hydroxy-4-cholesten-3-one>4-cholesten-3-one>7alpha-hydroxycholesterol>24-hydroxy-4-cholesten-3-one> cholesterol>25-hydroxy-4-cholesten-3-one>24-hydroxycholesterol>or=25-hydroxycholesterol. The possibility is discussed that the findings may have implications for oxysterol-mediated regulation of gene expression. The very high activity of CYP27A1 towards the cholestanol precursor 4-cholesten-3-one may be of importance in connection with the accumulation of cholestanol in patients with CTX.

Bile Acids and Salts↗