Signal-induced hydrolysis of inositol phospholipid produces two second messengers, diacylglycerol and inositol trisphosphate. Diacylglycerol activates protein kinase C, whereas inositol trisphosphate mobilizes Ca²⁺ from its internal store. Analogously, signal-induced hydrolysis of choline phospholipid generates two second messengers, unsaturated free fatty acid and lysophosphatidylcholine. The free fatty acid synergizes with diacylglycerol to activate protein kinase C and causes full activation of the enzyme even at the basal level of Ca2+. On the other hand, lysophosphatidylcholine dramatically enhances cellular responses such as cell proliferation and differentiation under the conditions where diacylglycerol and Ca²⁺ are available. It is likely that all of the immediate products of signal-induced degradation of inositol and choline phospholipids are involved directly in concert in the transmembrane control of cellular functions.

View full abstract

Covalent flavinylation as elucidated by the formation of the histidyl(N3)-8α-flavin bond in 6-hydroxy-D-nicotine oxidase of A. oxidans proceeds by an non-enzymatic mechanism. Incubation of the apoenzyme, FAD and a three-carbon phosphate ester at neutral pH leads to the formation of an enzymatically fully active holoenzyme. The role of His₇₁ in this process was illustarated by site-directed mutagenesis. Nevertheless, the question whether covalent attachment of the cofactor in a holoenzyme has prevailed throughout the evolutionary screening process because of biological significance or whether it is a chance event of neutral selective value [5] is still open.

View full abstract

The α-keto acid dehydrogenase multienzyme complexes play central roles in metabolism, are major sites of regulation, and are clinically important. Genes and cDNAs encoding the components of these complexes have been cloned and sequenced. Protein engineering and molecular cloning experiments are providing new insight into organization, structure-function relationships, and the molecular basis of genetic defects in these multienzyme complexes [11].

View full abstract

All eukaryotic cells and some prokaryotes that are unable to synthesize folic acid utilize membrane-associated transport systems for acquisition of the pre-formed vitamin or its coenzyme forms from external sources. These transport systems, in addition to providing folates essential for cell replication, are also important because of their role in the internalization of antifolates such as Methotrexate (MTX) that are used extensively in cancer chemotherapy. Information about the components and mechanism of folate transport systems has been derived, in large part, from studies with Lactobacillus casei and L1210 mouse leukemia cells, which serve as convenient models for prokaryotes and eukaryotes, respectively. L. casei contain a single folate transport system whose K_t value (i. e., concentration for half-maximum rate of uptake) for the preferred substrate folate is in the nanomolar range. The hydrophobic membrane-associated folate transport protein (18 kDa) has been purified to homogeneity and characterized. Expression of this transporter is repressed in cells grown on high concentrations (μM) of folate. L1210 cells contain two separate transport systems for folate compounds: (1) the low affinity system (K_t values for the preferred substrates 5-methyl- and 5-formyltetrahydrofolate and MTX in the μM range); and (2) the high affinity system (Kt for folate in the nM range). Fluorescein and biotin derivatives of MTX and folate, after conversion to N-hydroxysuccinimide esters, can be attached covalently to the transporters. These probes have been used for visualizing the transporters by fluorescence and electron microscopy and for their purification to homogeneity. The μM transporter (43 kDa) is a non-glycosylated, integral membrane protein, while the nM counterpart (39 kDa) is heavily glycosylated and anchored exofacially to the membrane by a glycosylphosphatidylinositol component.

View full abstract

Calcitriol-inducible C-24 oxidation in target cells gives rise to calcitroic acid in a variety of cells. The pathway probably involves a transient C₂₃-aldehyde intermediate. The pathway appears to play a crucial role in the duration of the 1, 25- (OH)₂D₃ signal in target cells. New analogs can be designed to render the molecule more susceptible or more resistant to target cell catabolism. However, these changes do not guarantee survival of the drug due to alternative degradatory pathways.

View full abstract

There is mounting evidence that essentially all fungi, plants and animals living on earth produce provitamin D. It is likely that once exposed to sunlight, these provitamins are converted to previtamin D. It is unclear why fungi, phytoplankton, zooplankton and plants have the capacity to produce such large quantities of provitamin D. It is likely, however, that provitamin D and possibly vitamin D play an important biologic role in these organisms. Buchala and Schmid [20] found, for example, that vitamin D₃ promoted adventitious root development. It may be that provitamin D has a more fundamental function in lower life forms. Provitamin D and its photoproducts have UV absorption spectra that overlap with the ultraviolet absorption spectra from ultraviolet radiation-sensitive macromolecules including DNA, RNA and proteins. Thus, provitamin D and photoisomers could serve as a photon sink, and therefore, act as a natural sunscreen to protect lower life forms from the damaging effects of the high energy ultraviolet radiation that they are exposed to.
It is more clear, however, that amphibians, reptiles, birds, mammals and humans all require vitamin D and that the vitamin D must be metabolized to 1, 25 (OH)₂D₃ before it can carry-out its physiologic functions on calcium and bone metabolism. The intense research activities during the past decade on the antiproliferative and differentiation activities of 1, 25(OH)₂D₃ has opened a new chapter for this vitamin/hormone [21-23]. 1, 25(OH)₂D₃ and its analogs are being developed for the treatment of psoriasis, breast cancer, and leukemia. As we approach the 21st century, it is likely that vitamin D compounds will be of clinical value not only for the treatment acquired disorders of 25-OH-D metabolism but also for the treatment of such diverse diseases as osteoporosis, arthritis, psoriasis, atopic dermatitis, cancer and as an agent to enhance wound healing.

View full abstract

The third component of complement (C3) is a protein produced by osteoblastic cells in response to 1α, 25(OH)₂D₃. The bone C3 appears to be involved in differentiation of bone marrow cells into osteoclasts in concert with other vitamin D-dependent factors. Further studies are needed to understand the precise role of C3 in bone.

View full abstract

A number of reports indicate that fish n-3 PUFA inhibit the development, growth and progression of several experimental tumors. There emerges a pattern of complex and diverse biochemical actions of n-3 PUFA in different animal tumor models, from the studies undertaken to date to evaluate the underlying mechanisms. These findings, along with the recent epidemiological evidence of an inverse correlation between fish intake and incidence of some human cancers, makes it worthwhile to determine the role of n-3 PUFA in cancer.

View full abstract

AA-2G is a new stable derivative of AsA which is efficiently synthesized by regioselective transglucosylation with α-glucosidase and CGTase. AA-2G serves as a vitamin C supplement in experimental animals. AA-2G is easily hydrolyzed in vivo by α-glucosidase and also synthesized as a metabolite under some specified conditions. AA-2G stimulates collagen synthesis in cultured fibroblasts and enhances antibody production in cultured splenocytes. AA-2G which has no cytotoxicity is a promising AsA derivative for medical and nutritional uses.

View full abstract

Biochemical and clinical evidence indicate that in situ kinetics is the first quantitative and achievable approach for determining optimal requirements for ascorbic acid, and for other vitamins.

View full abstract

Increasing evidence is accumulating that a synergistic role of the so-called antioxidant vitamins (C, E, B-carotene) may have a dominant role in the prevention of cancer, cardiovascular diseases and cataract formation.
Controversy still exists regarding the optimum intake of vitamin C. This is partly due to lack of accurate and easily accessible health-relevant endpoints, and lack of knowledge of the role of vitamin C in biochemical functions. Today, it is clearly recognized and broadly accepted that optimal health is a consequence of dietary optimization. Attainment of optimal health rather than prevention of deficiency symptoms is the goal. There can be little doubt that in this respect the requirements for vitamin C are greater than the amount required for the mere prevention of overt or classical scurvy.
The recommendation of varying levels of requirement could overcome the controversy. The following is therefore proposed:
The lowest level is that value which prevents deficiency symptoms.
The second level is valid for healthy populations (<200mg/d). This level would take into account needs which differ according to age, sex, physical activity, physiological status (e. g. pregnancy or lactation) and environmental factors such as smoking, pollution and alcohol intake.
Finally, a third level should be determined for the prevention of the above-mentioned non-communicable diseases. These diseases are an important cause of disability, resulting in costs of billions of dollars annually in medical costs. Many of the above-mentioned diseases can be prevented by supplementation with vitamin C. Medical costs could thereby also be dramatically reduced.

View full abstract

The effects of vitamin E on the progress of atherosc6lerosis in patients on hemodialysis was investigated clinically using ACI. There was a significant suppression of the increase in ACI in group A, compared to group B, at the time of observation in each year. On the other hand, no significant changes were noted in BWD, CTR, BP and blood chemical examination, except that the level of MDA was significantly decreased in group A as compared with that in group B 4 years later. Since ACI is an index representing atherosclerosis, the results of this study seemed to suggest that the progress of atherosclerosis was supressed by long-term administration of vitamin E in patients on hemodialysis.

View full abstract

Administration of vitamin E in doses of 400 IU/day exerts a potent inhibition of platelet adhesion as measured in a laminar flow chamber. Adhesion to all surfaces tested was reduced and appeared to be related to a limited pseudopodia formation in a-tocopherol-enriched platelets.

View full abstract

Vitamin E affects many key events in atheromatous lesions. Inhibition of EC injury and platelet aggregation was already reported. Foam cell formation must be inhibited according to the data presented by us and other speakers. However, effects on cell proliferation of SMC are paradoxical. The in vivo effects will be dependent on the effective concentration of vitamin E in the loci.

View full abstract

R292 is crucial for both the binding and the catalysis of the transamination reaction of dicarboxylic acid substrates. Substitution of R292 to uncharged residues greatly enhanced the catalytic efficiency of transamination of neutral amino acids without any effect on the binding. Residues at position 292 may not be involved in recognition of the neutral side chain. The indole ring of W140 not only regulates the rotational movement of the coenzyme ring during catalysis, but it also may be involvedin binding the carboxyl side chain of dicarboxylic substrates. The phenol group of Y70 is essential for the stabilization of the transition states with all substrates. Benzene ring at position 70 is necessary to recognize the glutamate-2-oxoglutarate substrate pair.

View full abstract