Structure folates

Table 4-5. The Folate Structures and Relative Inhibition Ability of Dihydrofolate Reductase...

As defined in the Introduction, Region E consists of the amide and a-carbon moieties jointly contributed by the p-aminobenzoyl and glutamate portions of the folate structure. Modifications of this region have been few and relatively... 

FIGURE 18.35 Formation of THF from folic acid by the dihydrofolate reductase reaction. The R group on these folate molecules symbolizes the one to seven (or more) glutamate units that folates characteristically contain. All of these glutamates are bound in y-carboxyl amide linkages (as in the folic acid structure shown in the box A Deeper Look Folic Acid, Pterins, and Insect VFingis). The one-carbon units carried by THF are bound at N, or at or as a single carbon attached to both... 

Methotrexate (MTX, chemical structure shown in Fig. 1.) competitively inhibits the dehyrofolate reductase, an enzyme that plays an essential role in purine synthesis. The dehydrofolate reductase regenerates reduced folates when thymidine monophosphate is formed from deoxyuridine monophosphate. Without reduced folates cells are unable to synthesize thymine. Administration of N-5 tetrahydrofolate or N-5 formyl-tetrahydrofolate (folinic acid) can bypass this block and rescue cells from methotrexate activity by serving as antidote. 

While the fluid mosaic model of membrane stmcture has stood up well to detailed scrutiny, additional features of membrane structure and function are constantly emerging. Two structures of particular current interest, located in surface membranes, are tipid rafts and caveolae. The former are dynamic areas of the exo-plasmic leaflet of the lipid bilayer enriched in cholesterol and sphingolipids they are involved in signal transduction and possibly other processes. Caveolae may derive from lipid rafts. Many if not all of them contain the protein caveolin-1, which may be involved in their formation from rafts. Caveolae are observable by electron microscopy as flask-shaped indentations of the cell membrane. Proteins detected in caveolae include various components of the signal-transduction system (eg, the insutin receptor and some G proteins), the folate receptor, and endothetial nitric oxide synthase (eNOS). Caveolae and lipid rafts are active areas of research, and ideas concerning them and their possible roles in various diseases are rapidly evolving. 

Sulphonamides are structural analogues of PABA. They competitively inhibit the incorporation of PABA into dihydropteroic acid and there is some evidence for their incorporation into false folate analogues which inhibit subsequent metabolism. The presence of excess PABA will reverse the inhibitory action of sulphonamides, as will thymine, adenine, guanine and methionine. However, these nutrients are not normally available at the site of infections for which the sulphonamides are used. 

One unwanted side-effect of phenytoin is its anti-folate activity. A programme of synthetic chemistry to manipulate the structure of the anti-folate compound pyri-methium to try to replace that property with anticonvulsant activity resulted in the synthesis of lamotrigine. It proved to be an effective AED in partial and generalised epilepsy but experience has found it also to be of value in absence seizures. 

Fig. 6.22. Folate-FRET sensor structure and its application to measure disulfide bond reduction in endosomes. The molecule contains the folate moiety which is recognized by the folate receptor situated at the plasma membrane. This recognition leads to endocytosis and after some time to cleavage of the probe. 

Fig. 11 Above Folate receptor-mediated targeting and SWNT-mediated delivery of structure 1 by endocytosis. Below. Structure 1. (Adapted from [60]).

Kraut, Crystal structures of recombinant dihydrofolate reductase complexed with folate and 5-deazafolate, Biochemistry 29 9467 (1990). 

A later paper65 reported a fluorescence maximum for leucovorin at 365 nm when excited at 314 nm in a pH 7 solution the concentration was 5 x 10-5 M. Variation between these data and other values was attributed to sample impurity, pH of solution, and quenching. The authors made an attempt to correlate structure and fluorescence of reduced folates. Similarity between tested compounds and jj-aminobenzoyl-glutamate lead them to conclude that this portion of the molecule is responsible for maxima at 360-425 nm when excited at 300-320 nm. They suggested that intensity differences may arise from various substitutions on the tetra-hydropteridine moiety. 

The N5 and N10 atoms which carry one-carbon groups are indicated Figure 5.8 Structure of folate... 

The chemical structure of folate (or folic acid) is shown in Figure 5.8. In humans, folate usually occurs as polyglutamate derivatives. The active form of folate is THF, sometimes shown as FH4) is derived from folate via two reductase reactions. THF functions as a carrier of one-carbon groups in varying oxidation states (Table 5.1). 

Figure 15.1 Structure of pterin. In the folates, pterin is linked to 4-aminobenzoic acid through at methylene bridge at posirion 6.

Figure 15.2 Structural formula of tetrahydrofolate and representation of derivatives involved in single carbon transfer. The tetrahydrofolate is always part of a complex with several glutamate residues. The parent compound, pteroylglutamate (folate) lacks four hydrogen atoms, one each from carbon atoms 5, 6, 7 and 8. Tetrahydrofolate can exist in any one of three oxidation states, as shown they are interconvertible through oxidereduction reactions. Each plays a individual and different role is synthesis of key compounds (See below).

Figure 22.6 How various factors increase the risk of atherosclerosis, thrombosis and myocardial infarction. The diagram provides suggestions as to how various factors increase the risk of development of the trio of cardiovascular problems. The factors include an excessive intake of total fat, which increases activity of clotting factors, especially factor VIII an excessive intake of saturated or trans fatty acids that change the structure of the plasma membrane of cells, such as endothelial cells, which increases the risk of platelet aggregation or susceptibility of the membrane to injury excessive intake of salt - which increases blood pressure, as does smoking and low physical activity a high intake of fat or cholesterol or a low intake of antioxidants, vitamin 6 2 and folic acid, which can lead either to direct chemical damage (e.g. oxidation) to the structure of LDL or an increase in the serum level of LDL, which also increases the risk of chemical damage to LDL. A low intake of folate and vitamin B12 also decreases metabolism of homocysteine, so that the plasma concentration increases, which can damage the endothelial membrane due to formation of thiolactone.

Vincristine has been shown to enhance the accumulation of the folate antagonist methotrexate in murine leukemia cells, and the enhancement has been shown to involve inhibition of a specific efflux route for methotrexate (25) the suggestion has been made that the effect of vincristine on methotrexate efflux may be related to alterations of cell membrane electrical activity that appear to occur when cells are treated with vincristine. In this connection, it is worth mentioning that association of tubulin with membrane structures from bovine brain has been described 25a). Both vinblastine and vincristine have been reported to enhance the accumulation of the folate antagonist methotrexate in human leukemic cells (S) there is no evidence, however, to indicate that this interaction has significance in a clinical setting. 

FIGURE 19.16 Sintetic structure of folates (folic acid). 

Para-aminosalicylic Acid (PAS), like the sulfonamides (see Chapter 44), is a structural analogue of p-aminobenzoic acid (PABA). It is a folate synthesis antagonist that interferes with the incorporation of PABA into folic acid. PAS is bacteriostatic, and in vitro, most strains of M. tuberculosis are sensitive to a concentra-... 

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