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The porphyrin handbook - Kadish K.M.

Kadish K.M. The porphyrin handbook - Academic press, 2000. - 368 p.
Download (direct link): kadishsmishgulilard2000.djvu
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transfer of electrons between the various cofactors which include FAD
(flavine adenine dinucleotide), FMN (flavine mononucleotide) and NADPH
(nicotinamide adenine dinucleotide phosphate), iron proto-porhyrin IX
heme, (6R)-5,6,7,8- tetrahydro-L-biopterin (H4B) and calmodulin. L-
arginine and H4B have been found to be the limiting factors of NO
generation. L-arginine analogues (including D-arginine) are not suitable
as substrates for NOS. Furthermore, analogues with subtitu-tions of one
or both of the amino nitrogen groups in the quanidino group (NG), for
example NG-monomethyl-L-arginine (L-NMMA), NG-nitro-L-arginie methyl
ester (L-NAME) and L-NG-nitro-L-arginine (L-NA), competitively inhibit
the formation of NO. Other inhibitors of NO generation include
flavoprotein binders (e.g., diphenylene iodonium), and carbon monoxide (a
heme binder).42
In the mammalian system there are two constitutive NOS isoforms,
neuronal (nNOS) and endothelial (eNOS), and one inducible NOS isoform
(iNOS). All three isoenzymes are homo-dimers. Each monomer has a
molecular weight ranging from 130,000 to 150,000 daltons containing four
prosthetic groups FAD, FMN, H4B and heme. The turn-over rate of NO
production for each monomer is 0.5-2 molecules per second. Since NO is
hydrophobic (solubility in water is only 2.82 mM) and is somewhat
lipophilic (KoW~6.5 at 37 C), NO freely diffuses rapidly through the
hydrophobic environment of cell membranes just like 02 and N2.41 In the
aqueous phase of the cytoplasm, the diffusion coefficient of NO is 3.6 x
10_5 cm-2s-1. Biosynthesized within the cell, NO may react with a select
few types of molecules
inside the cell, or outside (after free diffusion through the cell
membrane). The most rapid scavenger of NO is superoxide (02 , = 6.7 x
109 mol - 1s_1); the peroxyni-trite (OONO ) formed in this reaction is
quite stable, but when protonated (pKa = 6.8) usually it quickly
rearranges to H + and NO 43-45 Reaction with 02 is much slower and
leads to production of N0 + /N02 followed by further oxidation to N0 3 .
NO may also react with a few metal ions (iron, copper or manganese) which
are usually bound to proteins. The selective reactivity of NO with such
proteins, and its reaction with 2 and 02 dominate the chemistry of NO
in the biological systems 43-45
To date NOS has been found in many cell types in various parts of the
body. The monolayer of cells lining the cardiovascular system (the
endothelium) produce the largest amount of NO. The endothelium should be
considered one of the largest specialized organs in the body; the total
weight of endothelial cells in the human body is about 1.5 kg and is
comparable with the weight of a liver. In the brain, NO is produced by
both nNOS and eNOS. nNOS is also found in myocytes and skeletal muscles.
NO can also act as a cytostatic agent in the immune system. NO from iNOS
can be produced (after induction) by almost every cell in the human body,
where it plays a primary role in host defense. In this role, NO may
defend the body against invading bacteria, viruses and even cancer.
2. Nitric Oxide as a Regulator of the Cardiovascular System
Vascular endothelial cells contain calcium-dependent constitutive eNOS.
In order to maintain normal blood pressure, eNOS synthesize NO in bursts
lasting a few minutes. Synthesis of NO is stimulated by chemical agonists
like bradykinin, acetylcholine, ATP and several other agents that release
internal Ca2+ stores. Furthermore, physical agonists like shear stress,
flow, electrical current, light and electromagnetic fields can also
stimulate NO release in the cardiovascular system by causing the release
of internal Ca2+ stores, or opening ion channels to allow the relatively
large extracellular Ca2+ concentration into the cell.46 After eNOS is
turned on by Ca2+ flux and it biosynthesizes NO for about a minute, it is
turned off by phosphorylation of one of its serine residues. Then, it
rests for a few minutes, probably with the last molecule of substrate in
the active site, still arranging the eNOS conformation.
NO synthesized by endothelial cells diffuses out in all directions.
About 70-90% of NO released by the endothelium is washed away by the
blood where it is used to prevent platelet aggregation and the subsequent
formation of blood clots.47 The remaining amount of NO diffuses to the
wall of arteries and veins (smooth muscle) and triggers a cascade of
events leading to smooth-muscle relaxation. Relaxation of the surrounding
smooth muscle allows the blood vessel to dilate (increase of vessel
diameter), resulting in lowered blood pressure. The cardiovascular system
maintains a constant level of NO at a given blood flow 48 When blood flow
increases, the endothelium releases more NO to maintain its constant
concentration in the blood stream. When this normal level is not
produced, either because
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