Inflammation Pathways & the NADPH Steal€¦ · Inflammation Pathways & the "NADPH...

Fe2+PLP

SLC25A38/ABCB10

ABCB6

Prophobilinogen

Hydroxymethylbilane Protoporphyrinogen IX

Coporphyrinogen IIICoporphyrinogen III

Krebs Cycle

Proteins

Fatty Acids,Glycerol

Cholesterol

Carbohydrates

Amino Acids

Pyruvate Lactate

B1, B2, B3, B5, Lipoate

Acetyl CoA

OxaloacetateCitrate

Cis-Aconitate

D-Isocitrate

Malate

Fumarate

Succinate

Succinyl-CoA

Alpha-ketoglutarate

NADH

Complex I

Complex II

Complex III

Complex IV

O2

Mg

ACAT

Carnitine

Keto Acids

B1, B2, B3, B5, Lipoate

ACAT

ATP

Biliverdin Bilirubin

CO

HMOX

ROSStimulates

HMOX

Keap1 Nrf2

ATM

Ferritin

Glycine

ALAS

ALAD

HMBS

UROS URODCPOX

PPOX

Glyphosate

Molybdenum,B2

Low Heme resultsin Low Sulfate

Aldosterone

NOX

Luteolin Olive LeafApigenin

Stress

Glucose 6-Phosphate

G6PD

Glucose

HK

ADP

ATP

NADP+

NADPH

6-phosphogluconate

Pentose PhosphatePathway

NADP+

Excrete Potassiumand Hydrogen Ions

and hold Sodium

2 GSH

GSSGNADPH

NADP+

HEME

CO

NADPH &CYP450

Reductase

HEME

Biliverdin

NADPH &CYP450

Reductase

HEME

Ferritin

NADPH &CYP450

Reductase

Uroporphyrinogen III

Cysteine

CDOCysteineSulfinate

Fech

Homocysteine

CBS

Cystathionine

CTH HS-S2O3

2-

Thiosulfate

SO32-

Sulfite

SO32-

SO42-

Sulfate

SUOX

SUOX

CBS &CTH

Taurine

Taurine Spares Sulfur

Hypotaurine

SUOX isHeme Dependent

Homocysteine &Sulfites stimulate

NOX

Diet &Supplements

Preservativesand inhalingsulfur dioxide

PAPS3'-phosphoadenosine

5'-phosphosulfate

SULTPAPS

PAP

Excretedin Urine

Dopamine

Smoking

Iron

Angiotension II

Glutamate

Tryptophan N′-Formylkynurenine Intermediates

TDO,IDO1, IDO2

QuinolinicAcid

NADNAD+

NADP+

NADH

NADPH

NAMN

QPRT NMNATNAD

Kinase

ATP

ADP

ADP

ATP

HemeDe Novo Pathway

Dietary formsof Niacin

Preiss-Handler Pathway

Niacin &Nicotinamide Riboside

NAPRT

Pau D' Arco

NADS

CD38

Apigenin,Luteolin

NADPH

Krebs CycleKrebs Cycle

ME1

GTP

ALA

ALA

NADP+

NADPH

O2

NADP+

NO

Citrulline

NOS

Arginine

BH4Oxidative Stress

BH2

GPXSeSG

GPXSeSOH

GSH

GPXSeOH

H2O

H2O

TrxRed

TrxOXNADPH

NADP+

PrxSH PrxSOH PrxSOOH

PrxS-SPrx

H2O2

GlutathioneGSH reductase

Trx reductase thioredoxinSlow step

sulfiredoxin

H2O + O2

O2-

Cl-

HOCL

OH- + Cl-

Fe3+

Fe2+

Hypochlorous acid

NO

PeroxynitriteONOO-

ONOOH Peroxynitrousacid

iNOS

OH-

Heme Oxygenase(HO-1)

Polyunsaturated fatty acidsRO- + RO2

- Lipidhydroperoxides

β-carotenoidradical

β-carotene

OH O-

Ascorbate Dehydroascorbicacid

∝-tocopherol ∝-tocopherol

PARP

Malate

Pyruvate

Isocitrate

NADP+

NADPH

Alphaketogluterate

Heme

NADP+

NADPH

Glyoxylate

AGXT

Glycolate

Alanine

Pyruvate

GRHPR

NADPH NADP+

Oxalate

LDH

NADH

NAD+

GlyoxalateMetabolism

Histamine

Oxalates

HistamineRaising Foods

ABP1DAO

AllergensDiesel Exhaust

Histidine

HNMT

HDC

B6

SAMe

MAO

N-Methylimidazoleacetic acid

ImidazomeAcetaldehyde

ALDH

Imidazole acetic acid

Fats

Angiotension I

ACE

LF-EMF

Sulfites

mTOR

CurcuminSpirulina

CATCatalase

SODSuperoxideDismutase

Vasodilation andElectron Donor

Heme

Fe2+

HMOX-1

NOX

GSH NitrosoglutathioneNitric Oxide(reservoir)

BH4

BH2O2

-

Damage toProtein

Carbohydrateand DNA

Fe2

NADPH

CYP450 Reductase

Ammonia

Citruline

Arginine

ArginosuccinicAcid

AspartateOrnithine

Urea

SIRT1

Sirt3

AMPK

FOX03A

SOD2

IDH2

OTC(urea cycle)

CAT(Catalase)

P53

FOX01

NADPHSynthesis

SOD andAntioxidants

Glucose & OtherSugars

MastCells

Histamine

Cytokines

TNF-a

IL-13

LeukotrinesProsta

glandins

IgE

Luteolin &HMOX

KIT

To GlutathioneProduction

Homocysteine

CBS

Cysteine Glutamine

CTH

Sirt3

SIRT3 ControlsAMPK

y-Glu-Cys

GCLM& GCLC

Glycine

ATP

ADP

ATP

ADP

GSS

GSH(Reduced

Glutathione)

GSSG(Oxidized Glutathione)

GSR

GLRXNADPH

Xenobiotics

GST's

GSH-S-conjugate

Stool Urine

CYP 450

Phase 1Detox

Bile

MethionineMAT

AHCY

SAMe

SAH

BHMT

TMG

DMG

PEMT

MTRRMTR

B12

MTHFR

NRF2

Keap1Glutamate

GLS

GLUL

GABA

GAD

B6 and Magnesium

Excitatory - Simulates NOX Relaxing

InfectionInflammation

Chronic Stress andGlucocorticoid Elevations

Glutamine Synthase

Glutamate Synthase

Xenobiotics

BRCA1

FH

CDKN1A

Inflammation Pathways & the "NADPH Steal"

Glutathione Production

NADPH Production

Transsulfuration

Urea Cycle

FentonReaction

Fech HMOX

Genetics Variants Impacting Iron Dysregulation

FTL TFR2

HFE CP AC01 TF

SLC11A2DMT1

SLC40A1Ferroportin

Glycine +Succinyl-CoA

Zn2+

Lipoic Acid

Porphyrins will blockGABA receptors

FECH dependent oniron-sulfur clusters

Fe2+

FAD

PPIX

Zn2+,P5P

Fe3+

Lead

Elevated HEME(if HMOX lessthan optimal)

Poor conversionwill limit Heme

Nrf2

Glutathionereleased from

HEME

mTOR Stimulation

GrowthHormones

Glutamine

IronPlastics

Xenoestrogens

FolateDairy/Amino

AcidsInsulin/Carbs

Porphyrins andProtoporphyrins

GABAReceptors

Anxiety if blocked

Copyright 2018

Contributors to this map creation were:

Robert Miller, CTNMatthew MillerLari Young, MDEmily Givler, DSCBeth O'Hara, MAMackay Rippey, LAc

Reproductions of this map withoutpermission of NGRI is forbidden.

This pathway map is for informational, educational and research purposes only.

This map was not intended to provide diagnosis or treatment for any disease,and all users of this map agree to hold NGRI and the creators of this pathwaymap harmless for how they may use it.

Although great care was taken to ensure accuracy, errors may have occurredor further research or findings may contradict the pathways and interactions.

Nrf2

HemeCu, Zn

HemeMn

Nrf2

Nrf2Heme

Very high doseNicotinamide

Leptin ResistanceIGF-1

Vitamin DReceptor

Sirt1 potentiatesVit. D Receptor

DNA Repair

alpha-ketogluterate

GDH

GDH

Glutamate toAlpha-ketogluterate

OrnithineTranscarbamylase

ResveratrolBerberine

SIRT3 activates AMPK

Autophagy

Phase IIGlutathione Conjugation

Phase IISulfation

Borrelliaburgdorferi

DARC

DNA Repair

Oxalates stimulateNADPH Oxidase (NOX)

Succinyl-CoA To Heme Cycleto produce Heme

May simulateMast Cells

Catecholamines,Hormones,

Xenobiotics &Toxins

Pantethine

PANK

Deactivation and bioactivation of xenobioticsInactivation of hormones and catecholaminesStructure and function of macromoleculesElimination of end products of catabolism

OTC

ARG1

ASS1

ASL

SIRT3 StimulatesOTC

Folate Cycle

Shared in NOS Cycle

NOS

Tryptophan Tyrosine

Serotonin Dopamine

NitricOxide

Ammonia will deplete BH4 ifUrea Cycle weak or overwhelmedBH4

NOX Homocysteine canstimulate NOX to make free radicals

MastCells

Phase IIDetox

Norepinephrine

Epinephrine

MAO

COMT

Homovallinate

COMT

COMT

VMA

VMA

SAMe & Mg

SAMe & Mg

SAMe & Mg

LipidPeroxidation

VasodilationAnti-inflammatory

NOX Excess Dopamine will stimulateNOX and mast cells

Phase IIMethylation

NAT

Toxin, Xenobiotic

Ac-CoA CoA

Excretion

Phase IIAcetylation

NAT

Ac-CoA

CoA

Acetyl-Histamine

B6

Methylation andPhase II Methylation

StimulatesInhibits

Enzyme

Contributes to inflammationor mast cells degranulation

Food or Supplement

Co-factor

Free Radical

Free Radical or Damaging

Legend

NOX

HemoglobinMyoglobinNeuroglobinCytochrome p450Chtochrome c -Electron TransportPeroxidaseCatalaseNADPHTryptophan PyrrolaseNitric Oxide SynthaseSUOX

HEME plays a role in each of these

HEME

Heme

Byproduct ofKrebs Cycle

Bilirubin

Glutathione

ThioredoxinDHFR QDPR

N-MethylHistamine

Autophagy

GTPCH

Dietary &Supplemental

Glutamine

Homocysteine

MOLD

IL-4

Cortisol

Coenzyme A Acetyl CoA

ACAT2

AdrenalGlands

Hypothalamus PituitaryCRH ACTH

MastCellsStress

SIRT3

NAD+

NADH

Cystathionine

Function

Organ orGland

IDH

IDH

α-KGDH

Aconitase

Aconitase

SCS

SDH

Fumarase

MDH

CitrateSynthase

CoA

FOLR1 FOLR2 SLC19A1

Food basedFolate

MTHFD1

FolicAcid

DHF

B2, B3

THF

10 Formyl THF

5-10 Methylene-THF

5-10 Methy THF

DHFR

DHFR

MTHFD1

MTHFD15 Methyl THF

HydroxylRadicals

Peroxynitrite

BH2SAMe QDPR

UreaCycle

GSH+ GSNO

ULK1

ULK2

ATG13

mTOR

Nrf2

CO

Carbon Monoxidestimulates PPP

Resveratrol &Turmeric

Berberine andLithium

NO GSH+ GSNO

Transports NO

GSSG GSH

GSNOR

NMDAAMPA

Binds with Glutamate

H2O2

O2-

Nitric Oxide

O2-

O2

Nitric Oxide

Melatonin

5-HIAA MAOA

NQO1

SIRT3 activates IDH2 tosupport NADPH production

IDH3

Resveratrol

EMF

DHFR

Phase IIAcetylation

The "NADPH Steal"

Represents one of the following:compound or molecule orvitamin or intermediate

HO

HO

HO

GSR GLRX

B3

B2

B1, B2, B3, B5, Lipoate

B3, Mg, Mn

Cysteine, Fe++

PARP is responsible for DNA repair