An iron hydroxide moiety in the 1.35 A resolution structure of hydrogen peroxide derived myoglobin compound II at pH 5.2.

The biological conversions of O(2) and peroxides to water as well as certain incorporations of oxygen atoms into small organic molecules can be catalyzed by metal ions in different clusters or cofactors. The catalytic cycle of these reactions passes through similar metal-based complexes in which one oxygen- or peroxide-derived oxygen atom is coordinated to an oxidized form of the catalytic metal center. In haem-based peroxidases or oxygenases the ferryl (Fe(IV)O) form is important in compound I and compound II, which are two and one oxidation equivalents higher than the ferric (Fe(III)) form, respectively. In this study we report the 1.35 A structure of a compound II model protein, obtained by reacting hydrogen peroxide with ferric myoglobin at pH 5.2. The molecular geometry is virtually unchanged compared to the ferric form, indicating that these reactive intermediates do not undergo large structural changes. It is further suggested that at low pH the dominating compound II resonance form is a hydroxyl radical ferric iron rather than an oxo-ferryl form, based on the short hydrogen bonding to the distal histidine (2.70 A) and the Fe...O distance. The 1.92 A Fe...O distance is in agreement with an EXAFS study of compound II in horseradish peroxidase.

L-Phenylalanyl-L-alanine dihydrate.

A new type of molecular arrangement for dipeptides is observed in the crystal structure of L-phenylalanyl-L-alanine dihydrate, C12H16N2O3-2H2O. Two L-Phe and two L-Ala side chains aggregate into large hydrophobic columns within a three-dimensional hydrogen-bond network.

Nanotube formation by hydrophobic dipeptides.

A wide range of applications has been suggested for peptide-based nanotubes, which first attracted considerable interest as model systems for membrane channels and pores. The intriguing and unprecedented observation of nanotube formation by supramolecular self-assembly of the four dipeptides L-Leu-L-Leu, L-Leu-L-Phe, L-Phe-L-Leu and L-Phe-L-Phe is described here. These simple compounds crystallize with hydrogen-bonded head-to-tail chains in the shape of helices with four to six peptide molecules per turn. The resulting structures have chiral hydrophilic channels with a van der Waals' diameter up to 10 A.

An NH3+...phenyl interaction in L-phenylalanyl-L-valine.

One of the amino H atoms of L-phenylalanyl-L-valine, C(14)H(20)N(2)O(3), participates in a rare secondary interaction in being accepted by the aromatic ring of the phenylalanine side chain. The phenyl group is also a donor in a weak hydrogen bond to the peptide carbonyl group.

Selective solvent inclusion as a tool for mapping molecular properties in crystal structures: a diethylstilbestrol example.

Useful information about hydrogen bonding, the preferred modes of hydrophobic interaction and conformational preferences of a specific molecule can be obtained from cocrystallization of the solute with a selected series of solvent molecules. This method is used in a study of nine different crystal structures of diethylstilbestrol (DES) solvates. It is shown that solvent inclusion results not only in stronger hydrogen bonds, but usually also in a larger number of favorable C-H.pi interactions between DES molecules. Furthermore, solvent molecules such as DMSO, DMF, acetonitrile and acetone demonstrate important hydrogen-bond donating properties in addition to their more familiar role as hydrogen-bond acceptors. Molecular conformations in the crystal structures compare favorably with results from molecular mechanics calculations.

Non-centrosymmetric racemates: space-group frequencies and conformational similarities between crystallographically independent molecules.

DL-Allylglycine (DL-2-amino-4-pentenoic acid, C5H9NO2) yields crystals with Pca2(1) symmetry and two crystallographically independent yet pseudo-inversion-related enantiomers. The distribution among the common space groups of other crystalline racemates with more than one molecule in the asymmetric unit has been established. The conformational similarities between crystallographically independent enantiomers in 114 non-centrosymmetric racemates were quantified using the r.m.s. deviation for a molecular superposition. The analysis shows that in the majority of crystals the conformations of the crystallographically independent molecules are very similar with mean r.m.s. deviation = 0.190 A. In almost 80% of the structures the mean r.m.s. deviations is in the interval 0-0.2 A. It is estimated that racemates constitute 23% of the centrosymmetric organic structures in the Cambridge Structural Database.

Structural relationships in crystals accommodating different stereoisomers of 2-amino-3-methylpentanoic acid.

A reinvestigation of the crystal structure of the 1:1 mixture of the two racemates DL-isoleucine and DL-allo-isoleucine, with a detailed analysis of interatomic distances between alternative side-chain positions, reveals a systematic distribution of the four stereoisomers in this crystal. Two different molecular chains exist in the crystal and each such chain accommodates a single diastereomeric pair only (L-isoleucine:D-allo-isoleucine or D-isoleucine:L-allo-isoleucine). The crystal is built up by a stacking of such chains in two dimensions and three different packing modes for the two types of chains are discussed. Crystallization experiments of the two individual racemates in the 1:1 mixture of DL-isoleucine:DL-allo-isoleucine have been undertaken. The structure of the racemate DL-isoleucine is presented. The molecular arrangements in this racemate and the 1:1 DL-isoleucine:DL-allo-isoleucine mixture are closely related. Furthermore, the spontaneous resolution of enantiomers upon crystallization of the other racemate, DL-allo-isoleucine, is rationalized on the basis of the aforementioned analysis of interatomic distances in the 1:1 DL-isoleucine:DL-allo-isoleucine complex. Structural data for a new L-isoleucine: D-allo-isoleucine complex are also given.

Under-reporting of dietary intake by smoking and non-smoking subjects counselled for hypercholesterolaemia.

OBJECTIVES: We asked whether under-reporting of energy and cigarette smoking were associated with choice of foods and dietary composition amongst subjects with hypercholesterolaemia who had received dietary instruction to lower serum cholesterol. DESIGN, SETTING AND SUBJECTS: Dietary intake was assessed with a 4-day weighed food record in 205 women and 141 men, aged 20-73 years, being treated at a lipid clinic (tertiary referral centre). Under-reporting was assessed by calculating the ratio of energy intake (EI) to estimated basal metabolic rate (BMR). RESULTS: The median EI/BMR was 1.1 for both men and women. EI/BMR did not differ according to smoking status, but correlated negatively with body mass index (Spearman's rho = -0.32, P = 0.0001). EI/BMR was inversely associated with energy-adjusted intakes of potatoes, vegetables, fish and low-fat meats, and positively associated with intakes of nuts, potato crisps, chocolate, sour and ice cream, oils, fatty meat spreads, cakes and biscuits, and with alcohol. Thus, low EI/BMR was associated with increased energy-adjusted intakes of protein, thiamine, riboflavin, niacin, iron and cholesterol and with decreased intakes of sugar, poly- and monounsaturated fats and vitamin E (all P < 0.05). Cigarette smokers had a higher energy percentage (E%) from fat than non-smokers (29 +/- 6 vs. 26 +/- 6), a lower E% from carbohydrates (50 +/- 7 vs. 54 +/- 7) and a lower intake of vitamin C (11 +/- 7 vs. 16 +/- 9 mg MJ-1; all P = 0.0001), reflecting an increased intake of fatty meats and a decreased intake of skimmed cheese, fruit, rice and pasta, and cakes and biscuits (all P < 0.05). CONCLUSION: Weighed dietary records reflected a 'healthier' intake of fat, protein, sugar, alcohol and some micronutrients amongst under-reporters, suggesting that self-reported dietary intakes are biased in patients with hypercholesterolaemia. Lack of responsiveness to the diet should not be assumed when dietary data are based on self-report. Smokers report a higher intake of fat and lower intake of vitamin C than non-smokers, even after dietary counsel, and may require more intensive interventions to optimize the diet.

Results of intensive long-term treatment of familial hypercholesterolemia.

Fifty-seven patients with familial hypercholesterolemia (FH) with mean age of 48 years (range 30 to 69), participated in a follow-up examination 5.5 years after the completion of a 1-year trial with lovastatin, cholestyramine, probucol, or omega-3 fatty acids. The goals were to record quality of life, compliance to treatment, adverse effects, and clinical outcome. The quality of life was similar to that in a Norwegian reference population. The factors causing most distress to patients were keeping a diet low in saturated fats, taking medication, and fear of death. The medication was mostly prescribed in maximum dosages. At follow-up, the reduction in total cholesterol was 36% (p < 0.05), low-density lipoprotein (LDL) cholesterol 38% (p < 0.05), triglycerides 20% (p < 0.05) compared with being on diet therapy only. High-density lipoprotein (HDL) cholesterol increased 8% (p < 0.05). Intake of saturated and monounsaturated fat increased 1.5% and 1.7% (p < 0.05), respectively; polyunsaturated fat was unchanged. Three patients experienced myocardial infarction, of whom 2 died and 1 developed angina pectoris. Before the start of lovastatin treatment, 27 coronary events occurred per 1,000 patient-years in this group compared with 12 events per 1,000 patient-years thereafter. Of 28 patients reporting adverse events, 4 discontinued lovastatin and 3 discontinued cholestyramine. Several practical and psychological difficulties were associated with FH. Long-term intensive lipid-lowering therapy was possible in FH outpatients without loss of effect and with good compliance to therapy. Intensive therapy, today is, however, not sufficient for many FH patients to reach a therapeutic goal of LDL cholesterol < 4.0 mmol/L. More potent lipid-lowering agents are needed.

Glycyl-L-leucyl-L-tyrosine dihydrate 2-propanol solvate.

The asymmetric unit (C17H25N3O5.C3H8O.2H2O) consists of two crystallographically independent peptide molecules, A and B, with different conformations, chi 1(2) being trans and gauche- for the Leu residues in molecules A and B, respectively. The backbone conformation of both peptide molecules resembles that of the beta-pleated sheet arrangement found in proteins. Comparison with two other structures containing the tripeptide Gly-L-Leu-L-Tyr reveals almost identical molecular conformations, and in one instance also a common packing pattern.

Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women.

OBJECTIVES: To test the efficacy of hormone replacement therapy (HRT) and dietary therapy, compared to dietary therapy, in lowering LDL cholesterol levels among postmenopausal women. DESIGN: A prospective parallel randomized study of sequential 17 beta-oestradiol and norethisterone acetate or placebo for 48 weeks. SETTING: A University outpatient lipid clinic. SUBJECTS: A total of 76 postmenopausal women, aged 43-60 years, with LDL cholesterol levels > or = 4.2 mmol 1-1, treated with a lipid-lowering diet. MAIN OUTCOME MEASURES: Levels of lipids, lipoproteins, apolipoproteins, fibrinogen and glucose tolerance. RESULTS: Adherence to the diet was similar in both groups. Total and LDL cholesterol levels were reduced by 14% (95% CI, 11-17%) and 19% (95% CI, 14-23%), respectively, in the HRT group vs. 3% (95% CI, 0-7%) and 5% (95% CI, 0-11%) in the diet group. HRT reduced the levels of apolipoprotein B and lipoprotein(a). Levels of HDL cholesterol, HDL2, HDL3, triglycerides, lipoprotein populations and apolipoproteins AI and AII remained unchanged. No adverse effects on glucose tolerance or on fibrinogen levels were observed. The reduction in LDL cholesterol was positively correlated with initial levels of LDL cholesterol and negatively correlated with body mass index. CONCLUSIONS: HRT is effective in reducing elevated LDL cholesterol levels, and should be considered in the treatment of hyperlipidaemic postmenopausal women, in addition to dietary therapy.

[Diet and lipid status in pregnant women]. / Kosthold og lipidstatus hos gravide kvinner.

Pregnancy increases the requirement for nutrients and changes the metabolism of lipids and other compounds. We investigated the dietary composition and followed the changes in serum lipids during pregnancy among 20 women age 25-36 years. The women's diet was stable during pregnancy, but the intake of vitamin D, iron and fibre was lower than the national recommendations. Fat provided about 31% of the energy, saturated fat 12%. The total cholesterol concentration rose from 4.4 (95% confidence interval 4.2-4.6) to 7.0 mmol/l (6.5-7.5) (p < 0.0001) without changes in dietary composition. Even in this group of health-conscious, pregnant women the diet did not meet the national dietary recommendations. In addition, the composition of the fat in the diet was unfavourable. Optimal follow-up of pregnant women should include dietary counselling.

Is dietary intervention effective in post-transplant hyperlipidaemia?

Current therapies for hyperlipidaemia following renal transplantation include modification of dietary fat. We examined the effect of dietary intervention according to the American Heart Association Step One diet on serum lipids and lipoproteins among 26 men and women with post-transplant hyperlipidaemia. Weighed dietary records showed that the intake of total fat decreased from 30 to 27% and the intake of saturated fat decreased from 12 to 8% of total calories. Body-weight remained stable throughout the study. Serum total, LDL and HDL cholesterol levels were unchanged following 12 weeks of therapy. Serum triglyceride levels decreased slightly. The decrease was seen only in participants with a body mass index < 26 kg/m2, compared to those whose body mass index was > or = 26 kg/m2 (0.4 versus 0 mmol/l; P = 0.03). Serum LDL cholesterol and triglyceride levels were significantly correlated with serum creatinine levels. In conclusion, among renal transplant recipients, hyperlipidaemia appears to be partly related to impairment of renal function, and may not be responsive to modification of dietary fat without weight reduction attempted on an outpatient basis.

[Diet therapy of hypercholesterolemia. Can the diet of persons who already follow a cholesterol-lowering diet be further improved by guidelines given by a clinical nutritionist?]. / Kostbehandling ved hyperkolesterolemi. Kan kostholdet til personer som allerede følger et kolesterolsenkende kosthold, forbedres ytterligere etter veiledning av klinisk ernaeringsfysiolog?

The objective of the study was to investigate whether expert advice from a clinical nutritionist improves the diet of patients who have previously been instructed by health professionals to follow a lipid-lowering diet. We investigated dietary composition before and after dietary intervention by a clinical nutritionist in 46 individuals, aged 33 to 65 years, with primary hypercholesterolemia. After intervention, there was a 25% reduction in the intake of saturated fat and of cholesterol (p < 0.0001) and an 65% elevation of the P/S-ratio (p < 0.05). Percentage of energy from fat remained unchanged. The diet of patients who are already following a lipid-lowering diet can be improved by expert advice from a clinical nutritionist, and they easily adjust to new habits.

[A comparison between lovastatin and pravastatin--effects on lipids, sleep and quality of life in primary hyperlipidemia]. / Sammenlikning mellom lovastatin og pravastatin--effekt på lipider, søvn og livskvalitet ved primaer hyperlipidemi.

The efficacy and safety of treatment with recommended doses of lovastatin (20, 40 and 80 mg/day) and pravastatin (10, 20 and 40 mg/day) were compared in 48 men and women with primary hyperlipidemia and LDL-cholesterol > or = 4.1 mmol/l following dietary intervention. Each dose was taken for six weeks in this double-blind, parallel, randomized study. Lovastatin was found to reduce LDL-cholesterol by 22-37% and pravastatin by 18-26%. HDL-cholesterol levels increased and triglyceride levels decreased to the same extent in both groups. The number of patients who reported adverse events in the course of the study was small. No clinically significant changes occurred in laboratory tests, nor in sleep scores obtained from a standardized questionnaire. Neither drug had any effect on the responses to a quality of life screening questionnaire, nor were any significant changes in depressive symptoms seen during the 18 weeks of treatment.

[Iron status in postmenopausal women]. / Jernstatus hos postmenopausale kvinner.

Iron intake was determined in 42 postmenopausal women from food records over two three-day periods, with weighing of the food. The average daily intake was 9.4 mg (95% confidence interval 8.8-9.9). In 70% of the women the intake was lower than the nationally recommended 10 mg per day. Serum-ferritin was measured to detect possible iron deficiency. The average serum-ferritin was 60 micrograms/l (95% confidence interval 47-72). Only two women were advised to take iron supplements. One of these women had a serum-ferritin below 12 micrograms/l, which is regarded as empty iron store. A low iron intake in postmenopausal women is not an indication to prescribe iron supplements. Iron deficiency can be assessed only by serum-ferritin measurements.

NMR and molecular dynamics study of the tripeptide L-pyroglutamyl-L-histidylglycine.

The 1H spectrum of L-pyroglutamyl-L-histidylglycine in DMSO-d6 and 1H and 13C NMR spectra in D2O at pH 4.26 to 8.90 have been analysed. 3JHH vicinal coupling constants were used to determine rotamer populations by means of the Karplus equation. Viable molecular geometries were obtained with the aid of molecular dynamics simulations including water as solvent. In DMSO and in aqueous solution at low pH two stable conformations were identified which both have an intramolecular hydrogen bond between the histidine side chain and the C-terminal carboxylate group.

Structure of a 1:1 complex between L-Asp-L-Phe and L-His-Gly.

Both molecules occur in slightly folded conformations, characterized by phi 2 = -93.7 degrees in L-His-Gly and an unusual phi 2 = 60.2 degrees in L-Asp-L-Phe. The peptide linkage of L-His-Gly displays a substantial deviation from planarity with omega 1 = -163.5 degrees. The crystal packing is arranged in thick hydrophilic layers separated by hydrophobic sheets composed of L-Phe aromatic side chains. There are numerous hydrogen bonds, including an extremely short contact [O...N = 2.532 (6) A] between the ionized L-Asp and L-His side chains.

Effectiveness of low-dose lovastatin combined with low-dose colestipol in moderate to severe primary hypercholesterolaemia.

The effect of the combination of low-dose lovastatin and low-dose colestipol was studied among 57 subjects with moderate to severe primary hypercholesterolaemia (total cholesterol > or = 7.0 mmol l-1). Following an 8-week dietary phase, participants were randomized to treatment with 20 mg of lovastatin combined with 5 g or with 10 g of colestipol, or to matching placebo. Baseline total cholesterol was 7.7 +/- 0.9 mmol l-1 after dietary stabilization. Total cholesterol levels were reduced to 5.6 +/- 0.7 mmol l-1 and 5.8 +/- 0.7 mmol l-1 after 4 and 8 weeks of treatment in the lovastatin 5 g-1 colestipol group, and 74% of the subjects achieved the goal of low density lipoprotein (LDL) cholesterol levels of > or = 4.0 mmol l-1. Among the lovastatin 10 g-1 colestipol group, total cholesterol was reduced to 5.4 +/- 0.5 mmol l-1 and 5.5 +/- 0.9 mmol l-1 following 4 and 8 weeks, and 80% of subjects achieved the LDL cholesterol goal. No change was seen in the placebo group. Thus, low-dose combination therapy with lovastatin and colestipol, in conjunction with dietary treatment, is effective in moderate to severe primary hypercholesterolaemia, and is well tolerated.