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PubMed1994

Electrostatic potential surface analysis of the transition state for AMP nucleosidase and for formycin 5'-phosphate, a transition-state inhibitor.

AMP nucleosidase hydrolyzes the N-glycosidic bond of AMP to yield adenine and ribose 5-phosphate. Kinetic isotope effects have been used to establish an experimentally based transition-state structure for the native enzyme and a Vmax mutant [Mentch, F., Parkin, D. W., & Schramm, V. L. (1987) Biochemistry 26, 921-930; Parkin, D. W., Mentch, F., Banks, G. A., Horenstein, B. A., & Schramm, V. L. (1991) Biochemistry 30, 4586-4594]. The transition states are characterized by weak reaction coordinate bonds to C1' and substantial carbocation character in the ribose ring. The N9-C1' bond to the leaving group is nearly broken and the adenine ring is protonated at the transition state. Formycin 5'-phosphate and other purine nucleoside 5'-phosphate analogues with syn-glycosyl torsion angles bind better than substrate, supporting a syn configuration in the enzyme-substrate complex and presumably in the transition state [Giranda, V. L., Berman, H. M., & Schramm, V. L. (1988) Biochemistry 27, 5813-5818]. Access to a geometric model of the transition state permits the analysis of its molecular electrostatic potential surface as enforced by the enzyme. Comparison of the molecular electrostatic potential surfaces for AMP, formycin 5'-phosphate, and the transition state reveals a striking similarity in the surface charges of formycin 5'-phosphate and the transition state. The enzyme-stabilized transition state for AMP hydrolysis is characterized by new positive electrostatic potential in the adenine ring as a result of protonation by the enzyme. This is closely matched by the protonated pyrazole ring of formycin 5'-phosphate. The molecular electrostatic potential surfaces of formycin 5'-phosphate and the transition state for AMP are similar and are likely to be a factor in the Km/Ki value of > 10(3) for formycin 5'-phosphate as a transition-state inhibitor of AMP nucleosidase.

Electricity↗
PubMed1995

Compartmental analysis of colonic transit reveals abnormalities in constipated patients with normal transit.

1. The aims of this study were to investigate if compartmental analysis can be used to analyse colonic transit measurements and to search for a relationship between transit time and the parameters deduced from this analysis. In addition, an attempt was made to determine if such analysis could reveal a functional abnormality in patients who complain of constipation but have normal colonic transit. 2. The subjects included 11 healthy controls, 10 patients with chronic diarrhoea and 55 constipated patients. Segmental and total colonic transit time were measured using a previously described method. Compartmental analysis was based on a three-compartment system, with k1, k2 and k3 being the coefficients of diffusion out of the right colon, the left colon and the rectosigmoid area respectively. 3. Patients complaining of constipation who had delayed transit time were the only subjects to have lower values of coefficient k1 than controls. k2 was lower than normal in all patients complaining of constipation, but this decrease was more marked in subjects with delayed colonic transit time than in subjects with normal colonic transit time. All patients complaining of constipation had lower values of k3 than control subjects. 4. This study shows that analysis of colonic transit time is feasible using a simple diffusion law, and that the results are correlated to clinical data. Moreover, this analysis permits detection of abnormalities in two groups of subjects: those who complain of constipation but are labelled as having normal colonic transit time and those who have chronic diarrhoea.

Adult↗
PubMed2004

Gut transit in celiac disease: delay of small bowel transit and acceleration after dietary treatment.

OBJECTIVES: New studies indicate that body mass index (BMI) may influence gut transit. We studied gut transit and BMI in patients with celiac disease before and after treatment. METHODS: Twenty-seven (16 female) patients with untreated celiac disease were included for detailed gastrointestinal transit measurement and calculation of BMI. Ten patients (5 female) were also studied after dietary treatment. A newly developed radiological transit procedure was used. Eighty-three healthy subjects were used as controls. RESULTS: In untreated male patients BMI was significantly reduced compared to healthy males, and small bowel transit time (SBTT) was significantly longer compared with healthy males, 3.9 (1.2-5.5) versus 2.5 h (1.4-4.3), median and percentile 10 and 90, respectively, and p= 0.04. In the 10 men and women with repeated measurements, BMI increased significantly and small bowel transit accelerated after treatment and was 3.6 h (1.7-5.5) before treatment and 2.3 h (0.7-4.0) after treatment, and p= 0.007. In women, BMI did not differ significantly between untreated patients and healthy subjects, and 31% of the female patients were overweight. Small bowel transit was significantly faster in untreated female patients who were overweight compared with lean female patients. CONCLUSION: Small bowel transit seems to be delayed in lean patients with untreated celiac disease. BMI may have some influence on the variations of small bowel transit before and after treatment.

Adult↗
PubMed1996

Limitations of transition zone needle biopsy findings in the prediction of transition zone cancer and tissue composition of benign nodular hyperplasia.

OBJECTIVES: The transition zone of the prostate is the origin of 30% of all prostate cancers and of almost all benign prostatic hyperplasia (BPH). We compared histologic findings in transition-zone biopsies to tissue composition of the transition zone from radical prostatectomy specimens from the same patients to determine the efficacy of needle biopsies to evaluate either cancer or BPH. METHODS: A quantitative evaluation of the transition zone for both cancer and BPH in 21 retrospective and 11 prospective radical prostatectomy specimens was made. All retrospective cases had transition-zone biopsies prior to radical prostatectomy; all prospective specimen transition zones were biopsied after surgical removal with an ink-filled needle to trace the needle tracks after specimen processing. For all 32 specimens, total prostate weight, width of transition zone, transition-zone tissue composition, and epithelial/stromal (E/S) ratio of nodular and internodular BPH tissue were noted; the corresponding biopsies were evaluated for the amount of cancer and the composition of nodular and internodular tissue. RESULTS: Eight carcinomas larger than 5.0 cc were detected at biopsy, whereas 5 cancers smaller than 2.0 cc were undetected. Biopsies did not reliably predict BPH tissue composition or epithelial density of prostatectomy specimens; both were markedly underestimated. Dyed needle tracts showed selective sampling of internodular tissue versus nodules by biopsy as an explanation for low correlations. CONCLUSIONS: Transition-zone needle biopsies efficiently detect cancers larger than 5.0 cc and miss cancers smaller than 2.0 cc. Biopsies do not reliably predict BPH tissue composition because of selective sampling of the internodular tissue.

Biopsy, Needle↗
PubMed1993

Correlation of the molecular electrostatic potential surface of an enzymatic transition state with novel transition-state inhibitors.

The transition state stabilized by nucleoside hydrolase from Crithidia fasciculata is characterized by nearly complete glycosidic bond cleavage and oxycarbonium character in the ribosyl group [Horenstein, B. A., Parkin, D. W., Estupinan, B., & Schramm, V. L. (1991) Biochemistry 30, 10788-10795]. The electrostatic potential surface of the transition state provides detailed information which should be useful in the design of transition-state analogues [Horestein, B. A., & Schramm, V. L. (1993) Biochemistry 32, 7089-7097]. The electrostatic potential surface of inosine at the transition state contains a distributed positive charge resulting from the oxycarbonium ion character of the ribosyl ring. The ribosyl ring pucker is 3'-exo as a result of the near sp2 hybridization at Cl' of the ribose ring. A series of transition-state analogues have been synthesized which incorporate single or combined features of the transition state. Each feature of the transition state was analyzed for its contribution to binding energy. Kinetic inhibition constants correlate with the similarity of the inhibitor to the experimentally determined transition-state structure. Dissociation constants for the substrate and products of the reaction of inosine, hypoxanthine, and ribose are 380, 6200, and 700 microM, respectively. A transition-state analogue was synthesized which contains the required hydroxyl groups of the ribose ring, the positive charge feature of the oxycarbonium ion, and a hydrophobic mimic of the purine ring. The inhibitor 1(S)-phenyl-1,4-dideoxy-1,4-iminoribitol acts as a competitive inhibitor with respect to inosine with a dissociation constant of 0.17 microM. In addition, the inhibitor exhibits slow-onset inhibition which provides a final equilibrium dissociation constant of approximately 0.03 microM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Transition state structure of 5'-methylthioadenosine/S-adenosylhomocysteine nucleosidase from Escherichia coli and its similarity to transition state analogues.

Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes reactions linked to polyamine metabolism, quorum sensing pathways, methylation reactions, and adenine salvage. It is a candidate target for antimicrobial drug design. Kinetic isotope effects (KIEs) were measured on the MTAN-catalyzed hydrolysis of 5'-methylthioadenosine (MTA) to determine the transition state structure. KIEs measured at pH 7.5 were near unity due to the large forward commitment to catalysis. Intrinsic KIEs were expressed by increasing the pH to 8.5. Intrinsic KIEs from MTAs labeled at 1'-(3)H, 1'-(14)C, 2'-(3)H, 4'-(3)H, 5'-(3)H, 9-(15)N, and Me-(3)H(3) were 1.160 +/- 0.004, 1.004 +/- 0.003, 1.044 +/- 0.004, 1.015 +/- 0.002, 1.010 +/- 0.002, 1.018 +/- 0.006, and 1.051 +/- 0.002, respectively. The large 1'-(3)H and small 1'-(14)C KIEs indicate that the Escherichia coli MTAN reaction undergoes a dissociative (D(N)A(N)) (S(N)1) mechanism with little involvement of the leaving group or participation of the attacking nucleophile at the transition state, causing the transition state to have significant ribooxacarbenium ion character. A transition state constrained to match the intrinsic KIEs was located with density functional theory [B3LYP/6-31G(d,p)]. The leaving group (N9) is predicted to be 3.0 A from the anomeric carbon. The small beta-secondary 2'-(3)H KIE of 1.044 corresponds to a modest 3'-endo conformation for ribose and a H1'-C1'-C2'-H2' dihedral angle of 53 degrees at the transition state. Natural bond orbital analysis of the substrate and the transition state suggests that the 4'-(3)H KIE is due to hyperconjugation between the lone pair (n(p)) of O3' and the antibonding (sigma) orbital of the C4'-H4' group, and the methyl-(3)H(3) KIE is due to hyperconjugation between the n(p) of sulfur and the sigma of methyl C-H bonds. Transition state analogues that resemble this transition state structure are powerful inhibitors, and their molecular electrostatic potential maps closely resemble that of the transition state.

Carbon Radioisotopes↗
PubMed2007

Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise.

O-GlcNAcase catalyzes the cleavage of beta-O-linked 2-acetamido-2-deoxy-beta-d-glucopyranoside (O-GlcNAc) from serine and threonine residues of post-translationally modified proteins. Two potent inhibitors of this enzyme are O-(2-acetamido-2-deoxy-d-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc) and 1,2-dideoxy-2'-methyl-alpha-d-glucopyranoso[2,1-d]-Delta2'-thiazoline (NAG-thiazoline). Derivatives of these inhibitors differ in their selectivity for human O-GlcNAcase over the functionally related human lysosomal beta-hexosamindases, with PUGNAc derivatives showing modest selectivities and NAG-thiazoline derivatives showing high selectivities. The molecular basis for this difference in selectivities is addressed as is how well these inhibitors mimic the O-GlcNAcase-stabilized transition state (TS). Using a series of substrates, ground state (GS) inhibitors, and transition state mimics having analogous structural variations, we describe linear free energy relationships of log(KM/kcat) versus log(KI) for PUGNAc and NAG-thiazoline. These relationships suggest that PUGNAc is a poor transition state analogue, while NAG-thiazoline is revealed as a transition state mimic. Comparative X-ray crystallographic analyses of enzyme-inhibitor complexes reveal subtle molecular differences accounting for the differences in selectivities between these two inhibitors and illustrate key molecular interactions. Computational modeling of species along the reaction coordinate, as well as PUGNAc and NAG-thiazoline, provide insight into the features of NAG-thiazoline that resemble the transition state and reveal where PUGNAc fails to capture significant binding energy. These studies also point to late transition state poise for the O-GlcNAcase catalyzed reaction with significant nucleophilic participation and little involvement of the leaving group. The potency of NAG-thiazoline, its transition state mimicry, and its lack of traditional transition state-like design features suggest that potent rationally designed glycosidase inhibitors can be developed that exploit variation in transition state poise.

Acetylglucosamine↗
PubMed1997

Total prostate and transition zone volumes, and transition zone index are poorly correlated with objective measures of clinical benign prostatic hyperplasia.

PURPOSE: We determined if total prostate volume, transition zone volume or transition zone index is correlated with the severity of clinical benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: A total of 93 men 52 to 85 years old, who were referred to a urology outpatient facility for treatment of clinical BPH, elevated serum prostate specific antigen or abnormal digital rectal examination, underwent measurement of total prostate and transition zone volume at transrectal ultrasonography. All men were requested to undergo uroflowmetry and complete the American Urological Association (AUA) symptom score. RESULTS: The pairwise correlations between AUA symptom score, versus total prostate and transition zone volumes and transition zone index were not statistically or clinically significant. A weak pairwise relationship was observed between peak flow rate versus total prostate volume (r2 = 0.160), transition zone volume (r2 = 0.156) and transition zone index (r2 = 0.147). The pairwise relationships between AUA symptom scores versus all prostate volumes were not statistically significant for subjects with mild (score 8 or less) or moderate to severe (score more than 8) symptoms. CONCLUSIONS: Total prostate and transition zone volumes, and transition zone index are not directly related to AUA symptom score and only weakly related to peak flow rate. These findings provide further evidence that the total prostate, total BPH and relative BPH volumes are not useful determinants of the severity of clinical BPH.

Aged↗
PubMed2000

p53 mutations in prostatic intraepithelial neoplasia and concurrent carcinoma: analysis of laser capture microdissected specimens from non-transition and transition zones.

Prostatic intraepithelial neoplasia (PIN) is characterized by intraluminal proliferation of epithelial cells and is divided into high-grade (HGPIN) and low-grade (LGPIN) lesions. HGPIN is regarded as the most likely precursor of prostatic cancer (PCA). Microdissected DNA selectively extracted from paraffin-embedded sections of 27 cases with PCA were analyzed for p53 mutation in exons 5 - 8 by single-strand conformation polymorphism of polymerase chain reaction-amplified DNA fragments (PCR-SSCP) followed by direct sequencing. These patients received total prostatectomy (27 cases). After a review of histologic sections, DNA was extracted from 193 locations; 111 lesions from 27 cases with HGPIN (75 lesions from non-transition zone and 36 from transition zone), 55 lesions from 27 cases with PCA (30 lesions from non-transition zone and 25 from transition zone), and 27 from 27 benign glands. Analysis revealed 27 mutations of the p53 gene in 24 lesions from 12 cases. Benign glands adjoining PIN and / or PCA had no mutations. All mutations were point mutations: 17 missense, 7 silent, and 2 nonsense. Mutations were detected in 6 cases (22.2%) or 13 of 111 lesions (11.7%) with HGPIN and 8 cases (29.6%) or 11 of 55 lesions (20.0%) with PCA. In a given case, HGPIN and PCA lesions had different p53 mutations from each other, suggesting multiclonal development of prostatic precancerous lesions. The frequency of p53 mutation of PCA was significantly higher in the non-transition zone (33.3%) than in the transition zone (4%), and higher in the stage T3 cases (30.3%) than in the stage T2 cases (4.5%, 1 of 22 lesions) (both P < 0.05). Frequency of p53 mutation of PIN in the non-transition zone (14.7%) was higher than that in the transition zone (5.6%), although the difference was not significant. The frequency rate of p53 mutation in HGPIN close to PCA ( </= 2 mm) was significantly higher (24%) than that in HGPIN lesions > 2 mm from PCA (3%). All these findings indicate that the p53 gene mutations are involved in prostatic carcinogenesis and explain why the non-transition zone is the predominant site of PCA.

Genes, p53↗
PubMed1995

Whole-gut transit scintigraphy in the evaluation of small-bowel and colon transit disorders.

Scintigraphic methods for performing gastric emptying and colon transit studies are now well standardized. Although not as well established, several methods have been proposed for measuring small-bowel transit. The measurement of orocecal transit time appears to be a practical scintigraphic measurement of small-bowel transit. When combined into a single test of gastric emptying, small-bowel, and colon transit, whole-gut transit scintigraphy is an important, noninvasive tool for documenting dysmotility of any segment of the gastrointestinal tract. Despite attempts to simplify the study, whole-gut transit scintigraphy still requires a significant commitment of time and equipment. As with other gastrointestinal studies, each laboratory must determine which protocol best fits its clinical needs, equipment, and staffing. Attention must be paid to adhere to established protocols, or normal values will need to be determined for each laboratory. Despite these difficulties, whole-gut transit scintigraphy now represents an important clinical tool for the evaluation of patients with a wide range of abdominal complaints.

Colon↗
PubMed2001

Scintigraphic assessment of colonic transit in women with slow-transit constipation arising de novo and following pelvic surgery or childbirth.

BACKGROUND: Colonic transit has not been compared between patients with slow-transit constipation (STC) arising de novo (idiopathic) and those whose symptoms followed pelvic surgery or childbirth (acquired). METHODS: In 48 women, with either idiopathic (n = 36) or acquired (n = 12) STC, 111In-radiolabelled diethylene-triamine penta-acetic acid colonic scintigraphy was performed to determine patterns of delay (generalized or left sided), the 'severity' of transit disturbance between subgroups, and the association with age or duration of symptoms. Results were compared with those in healthy women. Patterns of colonic transit disturbance were assessed using previously defined criteria. In those with a generalized delay, variables reflecting the overall rate of isotope progression throughout the colon were calculated: gradient of geometric centre of isotope progression and estimated evacuation time of the isotope. RESULTS: The pattern of transit delay was similar between the subgroups, but the 'severity' of the transit abnormality was significantly worse in those with chronic idiopathic symptoms. In the chronic idiopathic STC subgroup only, there was a significant correlation between both age and duration of symptoms and severity of transit disturbance. CONCLUSION: This study demonstrates that differences in colonic transit exist between subgroups of patients with STC. These might be explained by differences in duration of symptoms or differences in aetiology.

Adult↗
PubMed2004

From transition paths to transition states and rate coefficients.

Transition states are defined as points in configuration space with the highest probability that trajectories passing through them are reactive (i.e., form transition paths between reactants and products). In the high-friction (diffusive) limit of Langevin dynamics, the resulting ensemble of transition states is shown to coincide with the separatrix formed by points of equal commitment (or splitting) probabilities for reaching the product and reactant regions. Transition states according to the new criterion can be identified directly from equilibrium trajectories, or indirectly by calculating probability densities in the equilibrium and transition-path ensembles using umbrella and transition-path sampling, respectively. An algorithm is proposed to calculate rate coefficients from the transition-path and equilibrium ensembles by estimating the frequency of transitions between reactants and products.

Algorithms↗
PubMed2005

Enzymatic transition states and transition state analogues.

Transition states are the balance point of catalysis. Bonds are partially made and/or broken at the transition state, and the energy of the extended system provides near-equal probability that the system forms products or reverts to reactants. Enzymatic catalytic sites provide dynamic electronic environments that increase the probability that the transition state will be formed. Alignment of reactants in the Michaelis complex and motion of the catalytic site architecture are necessary to achieve the transition state. Transition state lifetimes are a fraction of a picosecond, preventing chemical equilibrium in extended covalent systems. Thus, dynamic descriptions of enzymatic transition states are required. Stable analogues similar to the transition state capture dynamic excursions that generate the transition state and convert them into thermodynamic binding energy. These analogues bind with extraordinary affinity relative to reactants.

Animals↗
PubMed1991

Analysis and characterization of transition states in metabolic systems. Transition times and the passivity of the output flux.

In this paper we study the transitions between steady states in metabolic systems. In order to deal with this task we divided the total metabolite concentration at steady state, sigma, into two new fractions, delta (the Output Transition Time) and tau beta (Input Transition Time), which are related with the course of output and input mass to the system respectively. We show the equivalence time between these terms and the Total Transition Time, tau T, previously defined [Easterby (1986) Biochem. J. 233, 871-875]. Next, we define a new magnitude, the Output Passivity of a transition, rho, which quantifies a new aspect of the transition phase that we call the passivity of the output progress curve. With these magnitudes, all of them being experimentally accessible, several features of the transient state can be measured. We apply the present analysis to (a) the case of coupled enzyme assays, which allows us to reach conclusions about the progress curves in these particular transitions and the equivalence between tau sigma and tau delta, and (b) some experimental results that allow us to discuss the biological significance of the Output Passivity in the transition between steady states in metabolic systems.

Enzymes↗
PubMed2026

Transitioning to adult care for patients with IBD: the impact of a structured IBD transition program on service engagement.

BACKGROUND AND AIMS: The British Society of Gastroenterology recommend use of structured transition programs to improve control of chronic gastrointestinal disease in adolescents. We sought to determine the impact of attending a structured transition program on engagement of patients with inflammatory bowel disease (IBD) services and disease outcomes. METHODS: We performed a retrospective multicenter study of patients with IBD prior to and post-transfer to adult services. Patients were grouped into those who attended a structured transition program and those who received standard care, transferred with a referral letter. RESULTS: A total of 282 patients were included: 155 patients in our structured transition program cohort and 127 patients in the standard care cohort. Patients who took part in a structured transition program had significantly better engagement with adult IBD services with significantly lower rates of nonattendance at outpatient clinics 1-year post-transfer (12.3% vs 27.2%, P&#x2009;=&#x2009;.002) and significantly lower rates of disengagement with services (4.2% vs 13.1%, P&#x2009;=&#x2009;.015). There were no significant differences seen in rates of biologic failure, need for steroid/surgery or median fecal calprotectin levels between either group. Attending a structured transition program was the only factor that positively impacted engagement with IBD services in a multivariate analysis (OR 4.08, confidence interval 1.41-11.91, P&#x2009;=&#x2009;.01). CONCLUSION: Structured transition programs in IBD can improve engagement of patients with IBD services with significantly lower rates of disengagement with IBD services seen in our study. Large prospective studies are needed in this field to further investigate this and the impact of these programs on disease outcomes.

Humans↗
PubMed1994

Alpha/3(10)-helix transitions in alpha-methylalanine homopeptides: conformational transition pathway and potential of mean force.

The conformational transition between the alpha- and 3(10)-helical states of alpha-methylalanine homopeptides is studied with molecular mechanics. Conformational transition pathways for Ace-(MeA)n-NMe with n = 7, 9, and 11 are obtained with the algorithms of Elber and co-workers [R. Czerminski & R. Elber (1990) International Journal of Quantum Chemistry, Vol. 24, pp. 167-186; A. Ulitsky & R. Elber (1990) Journal of Chemical Physics, Vol. 92, pp. 1510-1511]. The free energy surface, or potential of mean force, for the conformational transition of Ace-(MeA)9-NMe is calculated from molecular dynamics simulations, and a method is presented for the decomposition of the free energy surface into the constituent energetic and entropic terms, via the calculation of the required temperature derivatives in situ. For the AMBER/OPLS model employed here, the conformational transition pathways each contain a single 3(10)-helical-like transition state, and the transition state potential energy relative to the 3(10)-conformation is 3 kcal/mol, independent of peptide length. Entropic stabilization in the barrier region significantly lowers the activation free energies for the forward and reverse transitions from the estimates of the barrier heights based simply on potential energy alone.

Alanine↗