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onsdag 14 september 2016

Gamma- voihappojohdannainen GABA

Kirjoitan  GABA-molekyylistä ikivanhan tekstin tähän, siis  Harperista, jonka avulla itse sain käsityksen gamma-aminovoihapon metaboliasta.
 Gamma-aminovoihappo  muodostuu  glutamaatista, kun  sen toinen -COOH pääty dekarboksyloituu. jolloin  jää jäljelle 4C- voihappo-runko, jonka  päätyhiilessä on NH2-ryhmä.
(H2N)C-CH2-CH2-COOH , gamma- amino voihappo,
Hiiliasemien nimet: C gamma  -  C beta-  C alfa -  C-pääty

Harper 1969 sivulta  350-2.

  • In the centrl nervous system  amino acid glutamate (GLU) plays a special role in brain metabolism. For example, the transport of potassium (kalium) to the brain is accomplished by glutamate. The role of glutamate (GLU) in detoxifying ammonia (NH3)  in the brain by formation of glutamine (GLN) should also be recalled. 
  • Decarboxylation of glutamate (GLU) produces gamma-aminobutyrate (GABA). An enzyme which catalyzes its formation from glutamte (GLU) by alpha-decarboxylation is found in tissues of the central nervous system, principally in the gray matter of the brain. This enzyme requires pyridoxal phosphate ( B6 vitamine)  as a coenzym.

(Comment: Glutamate COOH- CH(NH2)-CH2-CH2-COOH  has 5  carbon, The both ends have a carboxylgroup -COOH.
One of them decarboxylates. That means:  CO2- group leave the  molecule from the alfa- carbon)
GABA has 4 carbons left:
Compare (C4:0)  usual  Butyrate , short chain fatty acid, It has four carbons  C-C-C-COOH
but GABA has  still  NH2- aminogroup in the butyrate chain. Its place is called gamma, the third  carbon from the caerboxylated end of  this amino-butyrate-species:
(H2N)C-CH2-CH2-COOH , gamma- amino butyric acid)

  • Gamma-aminobutyric acid is now known to serve as a normal regulator of neuronal activity, being active as an inhibitor when studied in various reflex preparations. (1969!).
  • it is further metabolized by deamination to succinic semialdehyde. The deamination is accomplished by a pyridoxal-dependent enzyme and the ammonia removed is transaminated to ketoglutarate (alfa-KG) , thus forming more glutamate (GLU) 
(So You see  Glutamate  metabolism  (5 -carbon cycle)  can  recieve this toxic waste from GABA-metabolism  ( 4 c -cycle) with its  alfa-KG- metabolite ( 5 C metabolite)  , which can be enriched with nitrogenum waste  (NH3) and form thus  a new glutamate  molecule.  Even glutamate  can be enriched and  becoem glutamine.(GLN) with 2 nitrogens!


(And how the GABA itself  after  forming  succinic semialdehyd without nitrogen?)
  • Succinic semialdehyde may then be oxidized to succinate  ( and so  to take part in citron acid cycle, oxidative metabolism)  
  • or it can be reduced to gamma-hydroxybutyrate  GHB, which has been found to exist in the brain in significant amounts.  
( As we now some  drugaddicts "drink"  this  brain waste product,  the product of " brain tiredness" , "brain lactic  acid" relatively immense  amounts  with lethal  results and cannot wake up any more.  This  wasteproduct  metabolizes when people sleep  normally).
  • According to Fishbein et  Bessman (1964), reduction of succinic semialdehyde by homogenates of brain can be accomplished by an enzyme in the soluble protein fraction  which was indistingguishable from lactic dehydrogenase.
  • When succinic semialdehyde is oxidized to succinic acid, there is completed what amounts to a bypass around the citric acid  sycle in the brain in the sense that ketoglutarate (KG) , rather than going directly to succinate ( as in the citric acid cycle), is transaminated to glutamate (GLU) and thence by decarboxylation to gamma-aminobutyrate (GABA), which is the source of succinic semialdehyde to form succinate.  
  • Gamma-aminobutyrate has also been detected in the kidneys of humans, indicating that this compound is not unique of the central nervous system in man (1966). (Comment:  E.g.  pancreatic beta-cells use GABA-GLU cycle, when producing  glucose homeostasis to the bloodcircualtion).

Harper kuvaa vielä sivulla 522 aivojen ja hermon metaboliaa. Asetan sen kappakeen erikseen.

Koska kuitenkin GHB on kehitetty lääkkeelliseksi alunperin, otan siitä erikseen tekstiä.  GABA-neuronituhossa tai GABA-depletiossa sillä lienee merkitys lääkkeenä, kosa se on eräänlainen shunttitie saada GABA-molekyyliä aivoihin. Gatsa GHB,gamma- hydroksybutyrioc acid 

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