Harper esitti Glysiinin biosynteesin vuonna 1968 ja asetan sen vanhan tekstin tähän. Sivulta
GLYCINE (p.331) Siteeraan englantilasita tekstiä.
This aminoacid is nutritionally nonessential since it can be synthesized by many animals (but not the chick).
A. Deamination and transamination of glycine: CH2(NH2)COOH
Liver and kidney possess a sepcial flavoprotein, glycine oxidase, which oxidatively deaminates glycine to glyoxylic acid CH(O) COOH
CH2(NH2)COOH + 2H -> CH(NH)COOH Iminoacid (Intermediate)
(Oxidative reaction)
CH(NH)COOH + H2O -> CH(O)COOH + NH3 Glyoxylate
(Deamination reaction)
The deamination is readily reversible.
Transamination of glyoxylate using either glutamine(q), glutamate(e), asparagine(n), aspartate(d) or ornithine(ORN) as an aminodonor, produces GLYCINE (g) .
GLYCINE is glykogenic and antiketogenic. When glycine labeled with isotopic carbon* in the carbonyl group is fed, the carbon is found in the liver glycogen*, The amino nitrogen of glycine is exchanged readily with other amino acids. It has therefore been added in considerable quantities of mixtures of the essentil aminoacids for use in parenteral nutrition.
B. Special functions of GLYCINE
1. Synthesis of heme.
By the use of labeled glycine* it has been found that the alpha-carbon and nitrogen atoms are used in the synthesis of the porfyrin moiety of hemoglobin. The nitrogen in each pyrrole ring is derived from alfa-nitrogen and an adjoining carbon from the alpha-carbon* of glycine. the alpha-carbon* is also the source of the methylene bridges alpha*, beta*, gamma*, delta*) of the porphyrin structure. For every four glycine nitrogen atoms utilized, eight alpha-carbon* atoms enter the porphyrin molecule.2. Formation of Glycine from Choline by way of Betaine
The oxidation of Choline forms Betaine.
(CH3)3N-CH2-CH2OH, Choline
(CH3)3N-CH2-CHO , Betaine aldehyde
(CH3)3N-CH2-COOH, Betaine
Betaine is demethylated to Glycine by the loss of the first methylgroup in transmethylation, and the last two , by oxidfation to formate.
(CH3)2N-CH2-COOH , Dimethylglycine and CH3 (transmethylated)
CH3N-CH2-COOH, Sarcosine and CH2O Formaldehyde
NH2-CH2-COOH , Glycine and CH2O Formaldehyde
3. Conversion of Glycine to Serine
Glycine is readily converted to Serine. Tracer studies suggest the following mechanism. (Glycine gets "activate Formate-carbon" and become Serine)
CH2(NH2)COOH +activated Formate C*H2O > Serine , HOC*H2-CH(NH2)-COOH
The source of the Formate carbon which is added to Glycin to form beta-carbon of Serine has been studied 1956. Mackenzie has shown that a 50% yield of Serine occurs in the metabolism of Sarcosine by liver mitochondria. Tracer studies reveal that the beta-carbon of the Serine is derived from methyl carbon of Sarcosine. It is suggested , that oxidation of the methyl group produces "an active one -carbon moiety" ( "active Formaldehyde") , which either condenses with Glycine to form Serine or accumulates as formaldehyde. Labeled formaldehyde does not participate in the synthesis of of Serine in this mitochondrial system
The beta-carbon of Serine serves then as a source of methyl groups for Choline or Thymine synthesis. From the consideration of the above reaction it is apparent that this represents transfer of methyl groups by way of one-carbon(formate) moiety utilizing Glycine and Serine as carrier molecules. This tyoe oif methyl carbon transfer bas been called "transformalation" by mackenzie.
Huom. Kirjan kuva esittää Glysiinin konversion Seriiniksi ja myös Seriinistä tiet takasin kohti Glysiiniä, sivu 336:
the conversion of Serine to Glycine involves the loss of the beta-carbon, giving an active one-carbon moiety for methylation or for purine synthesis. If Serine is decarboxylated, ethanolamine is formed.
Sivu 332 Serine decarboxylated (Missä organismissa tämä 1968 kaava on pätevä?)
HOCH2-CH2NH2 , ethanolamine
Figure: ethanolamine > Glycolaldehyde and NH3
HOCH2-CHO ,Glycolaldehyde
Oxidation ov Glycolaldehyde + B2 vitamin> Glycolate
HO-CH2-COOH Glycolate oksidation to Glyoxylate HC(O)COOH
Glyoxylate transamination to Glycine.
(Siis tässä tulisi Seriinistä Glysiiniä)
4. Synthesis of purines
The entire Glycine-molecule is utilized to form positions 4, 5 and7 of the purine skeleton.5. Synthesis of creatine.
The sarcosine (N-methyl-Glycine) component of creatine is derived from Glycine.6. A constituent of Glutathione
The tripeptide glutathione is compound of glutamic acid, cysteine and glycine. The nitrogen in Glutathione is not available for transamination. Note that the peptide bond is with the gamma-COOH of glutamate.7. Conjugation with Glycine
Glycine conjugates with Cholic acid, forming the bile acid Glycocholic Acid.With Benzoic acid it forms hippuric acid ( excreted in the urine). This reaction is used as a test of liver function.
8. Oxidation of Glycine
Two pathways for Glycine breakdown have shown,.One involves conversion to Serine, the other formation of Glyoxylate after deamination by Glycone oxidase. The further breakdown of Glyoxylate has been studied in rat liver and kidney ( Nakada 1953), where formate ( muurahaishappo, myrsyra) results from oxidative decarboxylation of glyoxylate.
CH(O)COOH + ½O2 -> HCOOH, Formate
Formate is oxidiczed readily by many tissues to Oxalate
HCOOH + ½O2 -> (COOH)2 , Oxalate ( oksaalihappo, oxalsyra)
Primary hyperoxaluria is a metabolic disease characterized biochemically by continous high urinary excretion of oxalate which is unrelated to the dietary intake of oxalate (1958).
The history of the disease is that of progressive bilateral calcium oxalate urolithiasis, nephrocalcinosis, and recurrent infection of urinary tract. (-> renal failure, hypertension).
The excess ocalate is apparently of endogenous origin, possibly from glycine, which, as shown above, after deamination forms glyoxylate, itself a direct source of oxalate. The metabolic defect in this disease is considered to be a disorder of glyoxylate metabolism associated with failure to convert glyoxylate to formate etc, or to convert it back to glycine by transamination, as shown above and below. (Fig. above: Gly; Glyoxylate ; CO2 and Formate
Formate ; Formyltetrahydrofolic acid and CO2.
Fig. below: Specific aminotransaminases)
As a result the excess glyoxylate is oxidized to oxalate.
Two specific aminotransaminases are known to catalyze conversion of glyoxylate to glycine:
a) Glutamic-glyoxylate-aminotransaminase ( Glycine and alfa-ketoglutarate)
b) alanine-glyoxylate aminotransaminase (Glycine and pyruvate)
In human liver, activity of alanine-glyoxylate aminotransaminase is about 20 times higher than that of the glutamic-glyoxylate aminotransamianse.
A deficiency of the alanine transaminase together with some impairment of oxidation of glyoxylate to formate may be the biochemical explanation for the inherited metabolic dicease, primary hyperoxaluria.
As might be expected , vitamin B6-deficient animals excrete markedly increased quantities of oxalate because the glutamic or alanine transaminase reactions are vitamin B6- dependent. The excretion of oxalate in B6-deficient rats can be anhanced by feeding glycine or by feeding vitamin B6 antagonists. (1959). However, administration of vitamin B6 has been benefits in clinical cases of endogenous hyperoxaluria.
(Välillä kommentti: Nykyaikainen kahvin liika käyttö aiheuttaa vajetta B6 vitamiinissa. Sillä voi olla välillistä vaikutusta kudosten glysiiniaineenvaihduntaan).
9. The succinate-glycin cycle .
The important role of Glycine in porfyrin and purine synthesis, suggests a relation of the metabolism of Glycine to Citric acid cycle (1955).These pathways for the metabolism of Glycine have summarized in "succinate-glycin cycle". Succinate ( meripihkahappo), as "active succinate" ( Succinyl-CoA) condenses on the alpha-carbon*atom of glycine to form alfa-amino-beta-ketoadipic acid. It is at this point that the metabolism of Glycine is (one way-)linked to the Citric Acid Cycle, which provides succinyl-CoA.(Tässä siis Glysiini inkorporoituu, osat hyödynnetään eikä ole. Glysiinimuoto ole palautettavissa vaan osaset joutuvat lopulta eritystiehen a) hemoglobiinin porfyriinirenkaan hajotessa, b) puriinirenkaan hajotessa, c) ureasykliin karbamyyliryhmän myötä . Sitruunahapposykli ei menetä näitä työkalujäseniään meripihkahapoa tai alfaketoglutraattia tässä Glysiinin työstämisessä).
Alpha-amino-betaketoadipic acid gives away CO2 (via Biotin, ATP, MG++, glutamine to Carbamyl and to ureacycle). and is converted to delta-aminolevulinic acid. This compound serves as a common precursor for porphyrin synthesis aswell as, after deamination, a carrier molecule ( alfa-ketooglutaraldehyde) for the introduction of the ureido carbons (2) and (8) into the purine ring.
Succinate and ketoglutarate, which may return to the citric acid cycle, are also formed.
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