Kinoliinihappo ja muita COVID-19 taudissa koholla olevia katabolisia välituotteita .

 On havaittu, että  COVID-19 taudissa on  fenokonversiotaq  aminohappojen ja metabolisten  välituotteiden määrissä.

Lisääntynein määrin esiintyviä COVID-19  potilailla ovat: 

 Glutamic acid, Glutamate  eli glutamaatti,  glutamiinihappo (E, glu), tämä on excitatorinen aminohappo. Rakenneaminohappo

Quinolinate, kinolinaatti (*), Kinoliinihappo, (QA)

Aspartic acid, aspartate,   aspartaatti (D, Asp), Excitatorinen aminohappo, rakenneaminohappo

Phenylalanine, fenylalaniinbi (F, phe), rakenneaminohappo, essentielli

Neopterin, neopteriini

Kynurenine, kynureniini (*) (KYN) 

Nicotinic acid, Nikotiinihappo (*) (NA)

5-Hydroxykynurenine, 5 hydroksikynureniini (*), (5-HK)

Alanine,  alaniini (A, ala), rakenneaminohappo

Proline, proliini, (P, pro), rakenneaminohappo

Taurine (**) tauriini, ei- rakenneaminohappo, aminosulfonihappo,

Lysine, lysiini, (K, lys), rakenneaminohappo, essentielli

Etanolamine, etanolamiini (EA),  seriinin (S, ser)   biogeeninen amini  

Alfa-amino-butyric acid*), (AABA), alfa-aminovoihappo, cystathioniinin (CSH) kataboliasta  homoseriinistä eteenpäin, (biomerkitsijäaine huonosta  glukoositoleranssista)

Glutamine, glutamiini , (Q, gln), rakenneaminohappo

Isoleucine, isoleusiini (I, ile), rakennehappo, essentielli. 

1-methyl-histidine, 1-metyylihistidiini, 1-Me-His.( telencephalon histidiinimuoto)

 Nicotinamide ribosyl  (*?)

Glycine, glysiini, (G, gly), rakenneaminohappo,  inhibitorinen aminohappo 

 Ornithine, ornitiini, ORN, ei-rakenneaminohappo, UREA-syklin osa 

Leucine, leusiini, (L, leu), rakenneaminohappo, essentielli) 

Serine, Seriini (S, ser), rakenneaminohappo, 

Tyrosine, tyrosiini, (Y, tyr), rakenneaminohappo, essentielli.

4-OH-proline, 4-hydroxyproline,  4-hydroksiproliini (Hyp), rakenneaminohappo, joka muodostuu posttranslationaalisesti  proliinista (P, pro)

Kynurenine acid (KYNA), kynureenihappo (*), neuroprotektiivinen  NMDA reseptorin kompetitiivinen antagonisti Gly-kohtaan. 

Arginine, Arginiini()R, arg), rakenneaminohappo,  UREA-syklin osa  

Methionine (**), metioniini, (M, met), rakenneaminohappo, essentielli.

Valine, valiini (V, val), rakenneaminohappo,  essentielli.

 

Kontrolleihin verrattuna vähentynein määrin esiintyviä COVID-19 potilailla ovat: 

 

Histidine, histidiini, (H, his),   rakenneaminohappo, toisille  essentielli

Tryptophane, tryptofaani (W, trp), rakenneaminohappo, essentielli

Xanthurenic acid, xantureenihappo (*),  tryptofaanikataboliasta B6 puutteessa.

Citrulline (Karbamylornithine),, sitrulliini, UREA-syklin jäsen,  ei-rakenneaminohappo.

5-OH-anthranilic acid,(5-HANA) 5-hydroksiantraniilihappo (*) tryptofaanikataboliassa kynureenitiessä .

Serotonin, 5-OH-tryptamine, , serotoniini,  biogeeninen aminimuoto tryptofaaniaineenvaihdunnasta.

Indole-3-acetic- acid indoli-3-etikkahappo (*), tryptofaanin normaaleja  eritysmuotoja.

Picolinic acid, picolinate, pikoliinihappo (*), nikotiinihappoisomeeri tryptofaanin aineenvaihdunnasta.

Asparagine, asparagiini (N, asn), rakenneaminohappo.

Threonine, treoniini, (T, thr), rakenneaminohappo, essentielli. 

5-hydroxy-indole-acetic acid,  5-HIAA, 5-OH-indolietikkahappo (*). Normaali erittyvä päätetuote  tryptofaanin aineenvaihdunnasta. 

NAD, (?*)

Alfa-Amino adipic acid, alpha-aminoadipate, aminoadipiinihappo, lysiinin (K, lys)  normaali aineenvaihduntatuote. ei-rakenneaminohappo, dikarboksyylihappo.

5-methyl-histidine,  5-metyylihistidiini, 5-Me-His, telencephalon histidiinejä.

Tryptofaanin aineenvaihduntaan kuuluvia (*)

Rikin (S) aineenvaihduntaan kuuluvia (**)Huom. Virus kiskoo epäorgaanista rikkiä rakentaen Fe/S klustereita viruksen  polymeraasikoneiston avuksi.  Tästä ilmenee AABA katabolinen rikitön muoto ilmeisesti.

 

 

 

 

 

 

https://www.sciencedirect.com/topics/medicine-and-dentistry/quinolinic-acid

Sitaatti kinoliinihaposta, jonka pitoisuudet on havaittu nousseen COVID_19 taudissa, kuten monen muunkin molekyylin pitoisuus tryptofaanin aineenvaihdunnasta.

 QA on 2,3-pyridiinidikarboksyylihappo, jota muodostuu tryptofaanin kataboliassa kynureniinitiessä. Koska tryptofaani, eräs essentielli aminohappo, pystyy menemään aivojen puolelle,  pääsee QA täten muodostumaan useissa  soluissa, jotka ovat ottaneet tryptofaania (  eli astrosyyteissä, makrofageissa, mikrogliasoluissa ja denriittisoluissa) ja  joissa  muodostuu kynureniinia.

Quinolinic Acid (QA)

J.L. McBride, ... J.H. Kordower, in Encyclopedia of Movement Disorders, 2010

Description and Mechanism of Pathogenesis

Quinolinic acid (QA) is a 2,3-pyridine dicarboxylic acid (C₇H₅NO₄). QA is produced following the metabolic breakdown of the amino acid tryptophan, via the kynurenine pathway. Tryptophan is able to cross the blood–brain barrier (BBB), and upon entering the brain, is taken up by astrocytes, macrophages, microglia, and dendtritic cells and converted into kynurenine.  enzyme,kynureninase,  kynurenine  is converted to  3-hydroxyanthranilic acid,  this is  converted into QA through a series of enzymatic( and non-enzymatic)  reactions.

 QA is normally present in extremely low, nanomolar concentrations in the brain and in cerebrospinal fluid and does not cause damage to the surrounding cells. However, it has been recently demonstrated that increased levels of QA can be produced by activated macrophages and microglia in the brain. 

Accumulation of endogenous QA has recently been implicated in the etiology of certain neurodegenerative diseases, especially those with a strong inflammatory component, such as Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), Alzheimer’s disease (AD), stroke, multiple sclerosis (MS), and epilepsy.

QA exerts its biological effects by binding to and potentiating Mg²⁺-sensitive N-methyl-d-aspartate (NMDA) receptors, which normally bind the neurotransmitter, glutamate. As such, QA acts as a glutamate agonist and can potentiate NMDA receptors to the point of excitotoxicity. Specifically, overstimulating this receptor subtype allows high levels of calcium ions (Ca²⁺) to enter the cell, activating enzymes such as endonucleases, phospholipases, and proteases. These enzymes can then go on to damage cellular structures such as components of the cytoskeleton, membrane, and DNA and ultimately cause cell death. QA administration induces both apoptotic and necrotic types of neurodegeneration. In addition to a loss of neurons, QA administration also leads to a robust increase in the number of astrocytes (astrocytosis) and reactive microglia (microgliosis) in the region of the lesion.

 HARPER:haen esiin vanhan kirjani ja katson miten kynureenitie menee.

Tryptophan ( essentielli aminohappo, rakenneaminohappo,  ravinnossa saatava, W, trp)

Aromatic aminoacid  decarboxylase:  tryptamine ( biog. amine)

Tryptophan pyrrolase, O2, Fe++: N-Formylkynurenine

(immuneactivation)

N-Formylkynurenine + H2O : Kynurenine (KYN)  ( stress substance)     and  +HCOOH

B6 Deficienbcy:  Xanthurenic acid ( unnormal metabolism)

Kynurenine->  Kynurenic acid (KYNA)  and  alfa-KG+ (NH3) . KYNA is neuroprotective and NMDAR antagonist in Gly site. 

Kynurenine + O2 + NADPH -> 3-OH-kynurenine (3-HK)

3-HK + Kynureninase + B6-PO4 -> 3-OH-antranilate (3-HANA)  and alanine

2-HANA + O2, -SH required -> alfa-amino-beta-carboxymuconic acid semialdehyde 

a)
alfa-amino-beta-carboxymuconic acid semialdehyde

 (rapidly decarboxylated to alfa-amino-muconic semialdehyde  , then

1)  ( in liver, B6,  enzymatically) ->alfa-hydroxy- muconic acid  semialdehyde

2) NAD+ ->>alfa-oxalocrotonate and NADH+H2

3) NADH+H+->> alfa-ketoadipate and NAD+

4) CoASH, NAD+ ->> Glutaryl-CoA and  CO2 and NADH+H+ 

5) CoASH -> 2 Acetyl-SCoA and CO2.

b)

alfa-amino-beta-carboxymuconic acid semialdehyde 

Spontaneous  non-enzymatic ring closure, neurotoxic  pathway (chorea Huntington type)

-> Quinolinate (QA or QUINA)  and H2O 

QA  - CO2 ( decarboxylation)  -> Nicotinic acid  (NA)

c) Also enzymatic pathway  in Liver;  B6 vitamin required.

From alfa-amino-beta-carboxymuconic acid semialdehyde

alfa-picolinate,  isomere of nicotinic acid