Histidine decarboxylase activity, inhibition

Hindered rotation, see Barrier to rotation Histidine decarboxylase activity, inhibition of, 438... 

Able to form Ag salt of lower solubility than AgQ in H2O. Therefore applications in photographic processes Inhibition of histidine decarboxylase activity Antifoggant for color films Anthelmintic activity Quenching for oil composition caialj si for the industrial isomerization of cis a, (3 unsaturaied carboxylic acids rubber vul-cankzate improver... 

Several inhibitors of histidine decarbos lase have been investigated extensively by Johnston and Kahlson and by Levine, including the action of NSD 1055 (4-bromo-3-hydroxybenzyloxyamin in humans. Levine and Watts also reported on the inhibition of histidine decarboxylase activity in vitro by norepinephrine and related compounds. This is in cirntrast to the work by Pearlman and Waton who demonstrated that injections of epinephrine into mice increased histamine formation by skin, lung and skeletal muscle, but not by stomach tissue. Apparently the source of histidine decarboxylase is of great importance as to the effects of inhibitors or potentiators. 

Decarboxylation of histidine to histamine is catalyzed by a broad-specificity aromatic L-amino acid decarboxylase that also catalyzes the decarboxylation of dopa, 5-hy-droxytryptophan, phenylalanine, tyrosine, and tryptophan. a-Methyl amino acids, which inhibit decarboxylase activity, find appfication as antihypertensive agents. Histidine compounds present in the human body include ergothioneine, carnosine, and dietary anserine (Figure 31-2). Urinary levels of 3-methylhistidine are unusually low in patients with Wilson s disease. 

There are two distinct pools of HA in the brain (1) the neuronal pool and (2) the non-neuronal pool, mainly contributed by the mast cells. The turnover of HA in mast cells is slower than in neurons it is believed that the HA contribution from the mast cells is limited and that almost all brain histaminergic actions are the result of HA released by neurons (Haas Panula, 2003). The blood-brain barrier is impermeable to HA. HA in the brain is formed from L-histidine, an essential amino acid. HA synthesis occurs in two steps (1) neuronal uptake of L-histidine by L-amino acid transporters and (2) subsequent decarboxylation of l-histidine by a specific enzyme, L-histidine decarboxylase (E.C. 4.1.1.22). It appears that the availability of L-histidine is the rate-limiting step for the synthesis of HA. The enzyme HDC is selective for L-histidine and its activity displays circadian fluctuations (Orr Quay, 1975). HA synthesis can be reduced by inhibition of the enzyme HDC. a-Fluoromethylhistidine (a-FMH) is an irreversible and a highly selective inhibitor of HDC a single systemic injection of a-FMH (10-50 mg/kg) can produce up to 90% inhibition of HDC activity within 60-120 min (Monti, 1993). Once synthesized, HA is taken up into vesicles by the vesicular monoamine transporter and is stored until released. 

Apart from exocytosis, presynaptic H3 autoreceptors also inhibit the synthesis of histamine at the level of nerve endings, at least in part through pathways distinct from those leading to the inhibition of release. One pathway is inhibition of adenylyl cyclase (Gomez-Ramirez et al. 2002 Moreno-Delgado et al. 2006) activation of cAMP-dependent protein kinase A by cAMP stimulates histamine synthesis through phosphorylation of histidine decarboxylase, and this stimulation is diminished when adenylyl cyclase activity decreases following activation of H3 autoreceptors and Gi/o proteins. 

Cacabelos. R. et al. (1991) Histidine decarboxylase inhibition induced by a-fluoromethylhistidine provokes learning-related l pokinetic activity. Agents Actions, 33.131-134. 

Apart from the similar distribution of the decarboxylase activities discussed above, further evidence that various aromatic L-amino acids are all decar-boxylated by a single enzyme is based on (a) failure to dissociate the activities during progressive purification of the enzyme (b) the occurrence of competitive substrate inhibition (r) the fact that all the decarboxylations are inhibited by the same inhibitors (d) under conditions which lead to changes in the ability of a tissue to decarboxylate one substrate, parallel changes occur in the ability to decarboxylate the other substrates. In practice, most of this evidence has been obtained by the use of histidine, DOPA and... 

HTP and DOPA decarboxylase activities of partially purified extracts of hog kidney it has been stated that these compounds do not also inhibit histidine decarboxylase. This statement is misleading, however, as it refers to results obtained by earlier workers using a histidine decarboxylase of bacterial origin . ... 

Werle suggested that the active centre of histidine decarboxylase might contain a carbonyl group, since the enzyme was inhibited by reagents such... 

Inhibition by Inactivation or Displacement of the Co-enzyme The function of pyridoxal phosphate as the co-enzyme of histidine decarboxylase depends on the ability of the aldehyde group to react with the a-amino group of histidine. However, the aldehyde group also reacts with a wide variety of amino acids, amines and carbonyl reagents. The specificity of the holo-enzyme-substrate interaction is therefore due to the apo-enzyme. The co-enzyme attached to the active centre is presumably in equilibrium with free co-enzyme in the surrounding solution. 

Activation of the inducible enzyme becomes detectable 0-5-1 hour after application of the stress, and it persists for periods which depend on the nature and intensity of the stimulus. Under exceptional circiunstances the high rate of induced histamine formatation may be sufficiently prolonged to result in the development of shock . On the other hand, when the degree of activation of histidine decarboxylase is inadequate, tissue damage may occur as has been observed in the kidneys of endotoxin-treated rabbits . If histamine produced by inducible histidine decarboxylase is indeed a mediator of the slow phase of inflammation , inhibitors of this enzyme might possess anti-inflammatory action. It is thus of considerable interest that the ability of one class of anti-inflammatory drugs, the acidic group, to inhibit specific histidine decarboxylase runs parallel to their clinical activity . 

Histidine decarboxylase induction - in vivo (IP, mouse) at 3.2 mg/kg vs. LPS-induced HDC activities. Interleukin-1 formation inhibition - in vitro, ICso 3.4 pM/L. 

That not only DOPA decarboxylase and 5-HTP decarboxylase, but also the histidine decarboxylase (having its optimum activity in the range pH 8-0-9 5) are the same enzyme is also suggested by inhibition studies, a-Methyl-DOPA, for example, is a potent inhibitor of all three enzymes other pc-methylamino-acids behave similarly . 

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