Krebsův cyklus - Citrátový ckylus - Citric acid cyclus - TCA
Krebsův cyklus
Synonyma
- Citrátový cyklus - CC
- cyklus kyseliny citronové - Citric Acid Cycle - CAC
- cyklus trikarboxylových kyselin - TCA
Význam
- Aktivita KC je úzce spojena s dostupností kyslíku
- Ve všech buňkách kromě erytrocytů
- Oxidována kyselina octová: do cyklu vstupuje jako acetyl-CoA
- Redukované koenzymy (3 NADH a 1 FADH2) jsou následně reoxidovány (regenerovány) v dýchacím řetězci
- Meziprodukty CC jsou doplňovány tzv. anaplerotickými reakcemi
- Zvýšením množství určitého meziproduktu se tak zvýší kapacita CC
- Může oxidovat více molekul acetyl-koenzymu A
Insulinoresistance of skeletal muscle
- In glucose-tolerant obese
- Reduced activity of oxidative enzymes
- Increase in activity of glycolytic enzymes [1]
- In NIDDM
- More severe insulin resistance of skeletal muscle [1]
Glycolysis a citrátový cyklus, glykogeneze
- Decreased in leg muscle biopsies of obese patients
- Pyruvate dehydrogenase
- glycogen synthase [1]
- Glukoza tedy není zcela spálena v citrátovém cyklu, ani z ní není uděláno tolik glykogenu, snáze a dříve proběhne lipogeneze
- Glycolytic/oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity [1]
Alzheimerova choroba
- Disturbances of energy production can create abnormal spilling of Krebs’ cycle byproducts into the urine. [9]
Chronic Fatigue Syndrome (CFS)
- Poor attention, memory loss, lack of concentration and depression
- Underlying cause of CFS may be an impairment in the production of mitochondrial adenosine triphosphate (ATP) [9]
- CFS patients have elevated blood levels of lactate
- Indicating suboptimal aerobic ATP production that can lead to fatigue and muscle aches. [9]
- Glucose, pyruvate, aspartate, propionate, and butyrate, stimulated lactate conversion to fatty acids [15]
- 2-n-butylmalonate inhibited fatty acid synthesis from pyruvate, but not from glucose and acetate, and decreased the stimulatory effect of pyruvate on acetate conversion to fatty acids. [15]
- v adipocytech potkanů
- Studies have shown administering specific Krebs’ cycle amino acid precursors and intermediates to stimulate energy production significantly reduce symptoms of CFS [9]
Svaly
- Accumulation of large amounts of metabolic anaerobic byproducts can lower intracellular pH, inhibit muscle contraction, and may cause acidosis.
- Hydrogen ions, interferes with muscle contractions and ATP energy release. [9]
- Metabolic fatigue from exercise occurs when the muscle’s need for ATP has outstripped production capacity. [9]
- Chronic acidosis in muscle tissue causes a negative nitrogen balance and loss of muscle protein. [9]
- Phosphates and the amino acid carnosine account for 90% of muscle buffering. [9]
- Alkaline salts of phosphor [9]
- Reduce lactic acid buildup
- Reduce intracellular acidosis to delay muscle fatigue
- Increase the concentration of 2,3-DPG (diphosphoglycerate) in red blood cells
- Speeds the release of oxygen from hemoglobin to muscles [9]
- Help in the phosphorylation of creatine to creatine phosphate to reform ATP [9]
- 1 to 3 grams of phosphates one hour prior to workouts improved psychomotor performance and prevented muscle fatigue [9]
- Phosphates lead to a 10% increase in VO2max, a 10% increase in maximal oxygen uptake and a 9% increase in power output at anaerobic threshold [9]
Enzymy a substráty
Pyruvát
- Reduced to lactate in the cytoplasm [9]
- Oxidized to acetyl CoA [9]
Supplementace - salt of pyruvic acid
- Can increase muscle endurance and promote fat loss [9]
- Significant amount of weight loss and fat loss in obese women on a low calorie liquid diet. [9]
- Through increasing both resting metabolic rate and fat utilization [9]
- Increase the amount of glucose that enters muscle cells from the circulating blood
- Increases in immediate available energy
- Increasing stored muscle glycogen levels for future energy
- Increase glucose extraction by almost 300% and muscle glycogen by 50% after one hour of exercise [9]
- Increases muscle endurance
- Improves cardiac efficiency [9]
Pyruvát dehydrogenáza (PHD) komplex
- Vzniká AcoA a CO2
Nutné kofaktory pro činnost
- Vitamín B1 - thiamin difosfát - TPP
- Kyselina lipoová = alfa-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid)
- Stimuluje pyruvát dekarboxylázu
- Koenzym A - CoASH
- Pro syntézu CoASH je potřeba vitamín B5 - k. pantothenová
- Flavin adenin dinukleotid - FAD
- Nikotinamid adenin dinukleotid - NAD+
Stimulace činnosti
- Pyruvát
- CaASH
- NAD+
- Inzulín
Inhibice
- NADH
- H+
- ATP
- Glukagon
- Acetyl CoA
- Ca2+
- Arsen
- Nedostatek vitamínu B1
- ?-ketoglutarate may be a limiting factor for PHD activity under normoxia [10]
- Prolyl hydrogenáza (PHD)
Acetyl Co A
- Vznik z:
- Leucines, tyrosine, phenylalanine
- V cytosolu - pro syntézu MK a TAG
- Vzniká intracelulární palmitát - tvorba TAG
- Oleát - nutný pro fluiditu membrán a sekreci TAG játry
- Elevace TAG v krvi
- Synt. cholesterolu
- Inhibice fosforylované hormon senzitivní lipázy
- Elevace LDL vč. malých oxidovaných
- Zvýšené lačné ApoB
Citrat syntáza - CS
- Acetyl group of acetyl CoA + oxaloacetate = citrate
- Key step in TCA cycle
- Ratio of glycolytic/oxidative enzyme activities
- Within skeletal muscle correlated negatively with insulin sensitivity
- HK/CS ratio = strongest correlation with insulin sensitivity [1]
- Vzniká citrát a teplo
Snížená
- In subjects with NIDDM [1]
- In muscle fiber of post obese 20% lower:
- Beta-hydroxyacyl-CoA dehydrogenase (HADH)
- CS [1]
- Sukcinyl-CoA
- Vzestupem NADH/NAD+
- Long chain acyl CoA
- Citrate
- ATP
- Vyšší NADH
- H+ (nedostatek O2 = buněčná acidóza = zástava cyklu)
- Nižší NAD
Zvýšená aktivita
- Estrogenní receptory E2 [1]
- Oxalacetát - OAA
- AcCoA
- Citrátsyntáza produkuje tolik citrátu, kolik jí dodáme OAA a AcCoA
- ADP
- Vyšší NAD-
Citrát
- Present to some extent in all plant and animal tissues
- First isolated by the German biochemist, Karl Wilhelm Steele in 1784
- citric acid relieve from
- Fatigue
- Poor digestion
- Cold and flu infections
- Asthma
- Hypertension
- cholesterol [9]
- Control by citrate would be expected to be absent in rapidly dividing tumors which characteristically have low mitochondrial levels of citrate [13]
TCC = tricarboxylate citrate carier = citrate carrier = CiC
- Citrát přenášen z MTCH do cytosolu cestou TCC
- A nuclear-encoded protein
- In the mitochondrial inner membrane
- Important role in hepatic lipogenesis
- Key component of the isocitrate-oxoglutarate and the citrate-malate shuttles
- High concentration of TCC
- In liver, pancreas, and kidney [3]
- Low or absent TCC
- In brain, heart, skeletal muscle, placenta, and lungs
- In diabetic, hypothyroid, starved rats
- In rats fed on PUFA - enriched diet [3]
Citrát v cytosolu buňky
- Blokuje glykolýzu
- Slouží k syntéze MK
Snížená aktivita TCC
- Rybí olej
přenašeč citrátu do jádra buňky
- Vznik Acetyl-CoA v jádru
- Pomocí HAT vazba Ac na histony
- Ovlivnění genové exprese:
- Glut 4, HK2, PFK-1, LDH-A
Aconitase
- Exprese enhanced by E2 [1]
- In brain - zvedli syntézu [1]
- V hypofýze pokles vlivem DES [1]
- Vzniká cis-aconitate a potom izocitrát
- Akonitáza obsahuje Fe2+
Inihibice
- Fluoracetát
- ATP
- Vyšší NADH
- H+
- Nižší NAD
Cis-aconitate
Izocitrát
Isocitrate dehydrogenase (ICDH)
- Klíčový regulační enzym
- Vzniká
- Oxalosukcinát a potom alfa-kteoglutarát
- CO2
- Z NAD+ vzniká NADH+ a H+
Nutné kofaktory
- Mn2+ nebo Mg2+
Stimulace
- E2
- In the brain
- Liver
- Kidney cortex [1]
- ADP
- Pokles poměru ATP/ADP
- NAD+
Inhibován
- ATP
- Vzestup poměru ATP/ADP
- Hromadí-li se NADH + H+ a FADH2
- Vzestup poměru NADH/NAD+
Oxalosukcinát
Alfa-kteoglutarát = alfa-KG = AKG = oxo-glutarate = 2-Oxopentanedioic acid = C5H6O5 = 2-Oxopentanedoicic acid = 2-Oxoglutaric acid.
- Ketone derivatives of glutaric acid [4]
Vznik AKG
- Transaminací glutamátu, který vzniká: [4]
- Glutamát dehydrogenázou z: [4]
- Hydrolýzou glutaminázou z:
- Glutaminu [14]
- Ammonia converted to glutamine by glutamine synthetase in the liver
- During metabolic acidosis, kidney glutaminase helps eliminate excess acid [14]
- Produces ammonia
- Combines with a proton = ammonium ion (NH4+) = excreted [14]
- Arginase
- Ornithine-?-aminotransferase
- Glutamate-5-semialdehyde dehydrogenase
- proline oxidase
- Spontaneous
- Glutamate formiminotransferase [14]
Využití v org.
- Nitrogen transporter in metabolic pathways [4]
- One of the most important
- Carried to the liver for urea cycle [4]
- Ammonia can be incorporated directly into ?-ketoglutarate to make glutamate [12]
- Glutamate serves as the precursor of glutamine, proline and arginine
- Glutamate family [12]
- Vznik glutamátu ev. potom i GABA [4]
- When the energy supply is high, it is advantageous to allow the concentration of a-ketoglutarate to rise, allowing the formation of glutamate [12]
- Alfa-Ketoglutarate is transaminated with glutamine - excitatory neurotransmitter glutamate [4]
- Glutamate can then be decarboxylated (requiring vitamin B6) into the inhibitory neurotransmitter GABA [4]
- Kolagen 1
- With molecular oxygen, alpha-ketoglutarate is one of the requirements for the hydroxylation of proline to hydroxyproline in the production of Type 1 Collagen [4]
- Creatine-alpha ketoglutarate [4]
- Bakterie
- Aspartate aminotransferase
- L-aspartate + 2-oxoglutarate = oxaloacetate + L-glutamate [5]
- Precursor of porphyrins
- Synthesis of the cytochromes and the blood pigments
- ?-ketoglutarate preferentially accumulates in SDH-deficient cells, probably because TCA cycle metabolism is impaired [10]
- ?-ketoglutarate may be a limiting factor for PHD activity under normoxia [10]
- Raising ?-ketoglutarate concentration promoting amino acid synthesis [12]
- Transported out of the mitochondria and in to the cytosol
- Precursor for other essential molecules e.g. amino acids [12]
- Glutamate,...
Nízké hladiny alfa-KG
- High ammonia and/or high nitrogen levels
Suplementace
- Anabolic and anticatabolic effects [11]
- To body builders
- Stabilizes blood glucose levels during exercise
- Nitrogen-sparing effect and a reduction in loss of lean body mass
- Helps reduce ammonium levels that may interfere with exercise performance.
- Kidney disease [16]
- Hemodialysis patients [4]
- Gastrointestinal disorders [16]
- Bacterial overgrowth [16]
- Intestinal toxemia [16]
- Chronic candidiasis [16]
- Ammonia formed in the muscle, kidney and brain combines with alpha-ketoglutarate and L-glutamate to reduce ammonia toxicity. [9]
- Ornithine alpha-ketoglutarate (OAKG or OKG)
- Ornithine and glutamine
- Alpha-ketoglutarate reduce problems associated with ammonia toxicity [4]
- Selhání jater [16]
- Cataracts [16]
- Chirurgie srdce
- Intravenously preventing ischemic injury during heart surgery
- Improving renal blood flow after heart surgery
- Preventing muscle protein depletion after surgery or trauma [16]
- Možnost zlepšení prevence a terapie osteoporózy:
- Možnost zlepšení terapie dyslipidémií (hypercholesterolémie, vysoké LDL, TAG):
- Možnost ovlivnění chronické infekce Helikobakterem pylori a zlepšení svalové síly:
- Možnost zlepšit výsledky redukce hmotnosti:
- Vliv na imunitní systém:
- Podpora při chemoterapii některých typů nádorů:
- Introduction of ?-ketoglutarate derivatives restores normal PHD activity and HIF1? levels to SDH-suppressed cells [10]
- Indicating new therapy possibilities for the cancers associated with TCA cycle dysfunction [10]
- Native ?-ketoglutarate does not readily enter cells
- Cell-permeating ?-ketoglutarate derivatives that are hydrolyzed in the cytosol can be used [10]
Další využití
- Adding ?-Ketoglutarate to Semi-hard Cheese Curd Highly Enhances the Conversion of Amino acids to Aroma Compounds [11]
Alfa - ketoglutarat dehydrogenase complex = oxoglutarate dehydrogenase complex (OGDC) = KGDH
- Vzniká
- Succinil CoA
- CO2
- Z NAD+ vzniká NADH+ a H+
- Sensitive to mitochondrial redox status
Komplex OGHDC
- Multiple copies of 3 enzymatic components:
- Alfa-ketoglutarate dehydrogenase component (E1)
- E1 and E3 are not bound to each other
- Transsuccinylase component (E2)
- Bound directly to both E1 and E3
- Core component of the complex [12]
- Dihydrolipoyl dehydrogenase component (E3) [12]
- Identical to it’s equivalent component in pyruvate dehydrogenase complex [12]
Nutné kofaktory
- Thiamindifosfát - vitamín B1
- Thiamin pyrophosphate (TPP)
- Bound to E1 and decarboxylates pyruvate
- Yielding a hydroxyethyl-TTP carbanion
- Prosthetic group is lipoic acid [12]
- K. lipoová
- Covalently linked to a Lys on E2 (lipoamide)
- Accepts the hydroxyethyl carbanion from TPP as an acetyl group [12]
- Transfer of electrons and activate acyl groups, resulting from the decarboxylation and oxidation of a-ketoglutarate within the complex [12]
- Dual role of electron and acyl-group acceptor
- Transiently reduced to dihydrolipoic acid
- The acceptor of the activated succinyl groups [12]
- H2O2 v MTCH reverzibilně inhibuje
- Glutathionylation of the cofactor, lipoic acid
- 4-Hydroxy-2-nonenal (HNE), a lipid peroxidation product
- CoASH
- Substrate for E2 and accepts the acetyl group from lipoamide [12]
- FAD
- Bound to E3 sub-unit which is reduced by lipoamide [12]
- NAD+
- Substrate for E3
- Reduced by FADH2 [12]
Stimulace
- Kyselina lipoová = alfa-Lipoic acid (LA; 5-(1,2-dithiolan-3-yl)pentanoic acid)
- ADP
- Ca2+
Inhibován
- ATP
- Vzestupem ATP / ADP
- Hromadí-li se NADH + H+ a FADH2
- vzestupem NADH / NAD+
- GTP
- Sukcinyl-CoA
- Arsenitan
Succinil CoA
Succinyl CaA syntetase
- Vzniká
- Succinate
- GTP z GDP (směněn za 1 ATP)
- Při degradaci acetoacetátu vzniká succinate jinou cesotu a nevzniká GTP
Succinate = C4H6O4 = HOOC-(CH2)2-COOH = 1,2-Ethanedicarboxylic acid = Amber acid = Asuccin = Bernsteinsaure = Butanedioic acid = Butanedionic acid = Spirit of amber = Kyselina jantarová = 1,2-Ethanedicarboxylate = 1,4-Butanedioate = Dihydrofumarate = Dihydrofumaric acid = Katasuccin = Wormwood acid = Bernsteinsaure
Vznik
- Z: val, met, ile
- Important in supplying the heart with fuel for myocardium contractions under low oxygen conditions [9]
Význam
- Local levels of succinate in the kidney
- Serves an electron donor in the production of fumaric acid and FADH2 [6]
- Succinate import into the mitochondrial matrix
- N-butylmalonate- (or phenylsuccinate-) sensitive dicarboxylate carrier [8]
- In exchange with inorganic phosphate or another organic acid, e. g. malate [8]
- GABA
- Oxidized to succinic acid for cellular energy production [9]
- Reduced to GHB [9]
- Combines with protein to rebuild muscle fiber and nerve endings [9]
- Helps fight infection [9]
- Chronic Fatigue Syndrome
- Low levels of succinic acid in their urine [9]
- Succinate is an inflammatory signal that induces IL-1ß through HIF-1 alfa [18]
- Lipopolysaccharide strongly increases the levels of succinate [18]
- Succinate enhances interleukin-1-beta production during inflammation [18]
Výskyt
- Occurs naturally in amber
- V buňkách lokalizována
- Extracellular
- Mitochondria
- Endoplasmic reticulum
- Peroxisome [8]
Metabolické dráhy
- Citric Acid Cycle
- Glutamate Metabolism
- Mitochondrial Electron Transport Chain
- Phytanic Acid Peroxisomal Oxidation
- Carnitine Synthesis [8]
Normální koncetrace
Využití
- Also used in foods as a sequestrant, buffer, and a neutralizing agent [6]
- Dietary supplement [6]
- Micronutrient [6]
- Radiation-Protective Agents [6]
- "natural" antibiotic because of its relative acidic or caustic nature (high concentrations can even cause burns) [6]
- Help reduce the effects of hangovers
- Activating the degradation of acetaldehyde - a toxic byproduct of alcohol metabolism - into CO2 and H2O through aerobic metabolism [6]
- Stimulate neural system recovery [6]
- Bolster the immune system [6]
- Boosts awareness, concentration and reflexes [6]
- Sand bath [7]
- Acidity regulator in food [7]
- Byproduct of the fermentation of sugar
- Fermented beverages
- Wine and beer - common taste [7]
- Combination of saltiness, bitterness and acidity
- Oil of amber, procured by heating succinic acid [7]
- Perfume esters
- Synthesis of polynuclear aromatic hydrocarbons
- Intermediate for dyes, perfumes, lacquers, photographic chemicals, alkyd resins, plasticizer, Metal treatment chemical, vehicle water cooling systems and coatings
- Plasticizer for polymers
- Biodegradable solvents and lubricants
- Engineering plastics
- Epoxy curing agent
- Adhesive and powder coating
- Corrosion inhibitor
- Perfumery and pharmaceutical
- Electrolyte
Succinate dehydrogenase = SDH
- Covalently attached FAD prosthetic group
- Binds enzyme substrates
- Succinate
- Fumarate
- Vzniká
- Fumarát
- Z FAD vzniká FADH2
- In the mitochondria
- Respiratory chain
- Forms complex II of the electron transport chain [10]
- Ve vnitřní mitochondriální membráně
- Umožňuje zapojení H+ a e- z FADH2 do dýchacího řetězce
- Krebs cycle
- Genetickými mutacemi v enzymu i: Huntington's disease [8]
- Tumor suppressor
Nezbytné koenzymy
Stimulováno
- DHT alone stimulated the activities
- E2 alone failed in castrated animals.
- E2 + DHT stimulation and the response of the rhesus monkey´s epididymis [1]
Inhibováno
- DES
- V hypofýze a játrech [1]
- V játrech glutamic-oxalacetic transaminase [1]
Classes of inhibitors of complex II:
- Bind in the succinate pocket
- Synthetic compound malonate
- Malate
- Oxaloacetate
- One of the most potent inhibitors of Complex II [17]
- Bind in the ubiquinone pocket
- Fungicides in agriculture
- Carboxin
- Control disease caused by basidiomycetes such as stem rusts and Rhizoctonia diseases [17]
- Boscalid
- Penthiopyrad
- Fluopyram [17]
- Thenoyltrifluoroacetone [17]
Důsledky inhibice:
- Loss of SDH or FH induces pseudohypoxia
- Major tumor-supporting event
- Activation of hypoxia-inducible factor (HIF) under normoxia [10]
- Enhanced neovascularization [10]
- Glycolysis [10]
- SDH dysfunction results in an accumulation of succinate
- Succinate inhibits (PHD) hydroxylation of HIF1-alfa [10]
- Excess of alfa-ketoglutarate, provided in a form that allows uptake by cells, overcomes PHD inactivation by succinate [10]
Důsledky mutací
- SdhA mutations
- Leigh syndrome
- mitochondrial encephalopathy
- Optic atrophy
- SDHAF1 mutations
- Leukoencephalopathy with onset during early childhood [20]
- Isolated complex II (CII, or SDH) deficiency [20]
- Increased succinate in the affected white matter [20]
- SdhB, SdhC and SdhD mutations
- Tumorogenesis in chromaffin cells
- Hereditary paraganglioma
- Hereditary pheochromocytoma
- Decreased life-span
- Increased production of superoxide ions [17]
- Cardiomyopathy [19]
- Exercise intolerance [19]
Fumarát
- Může vzniknout také z:
- Tyr, phe
- Trans-isomer of malic acid
- Byproduct
- Arginine-urea cycle
- Purine biosynthesis [9]
- In healthy individuals, fumaric acid is formed in the skin from exposure to sunlight. [9]
Nedostatek
- Deficiency of malic acid and fumaric acid is linked to chronic fatigue and psoriasis [9]
- Accumulation of metabolic half-products
- May be responsible for causing the skin lesions of psoriasis
- Psoriasis
- Biochemical defect
- Do not produce enough fumaric acid
- Requiring prolonged exposure to the sun [9]
Supplementace
- In psoriasis has caused a gradual elimination of the symptoms [9]
Fumarase
- Vzniká malát
- Tumor suppressor [10]
- Loss of SDH or FH induces pseudohypoxia
- Major tumor-supporting event
- Activation of hypoxia-inducible factor (HIF) under normoxia [10]
- Enhanced neovascularization [10]
- Glycolysis [10]
Malát
- Vzniká také z:
- Leucines, tyrosine, phenylalanine
- Acts as a catalyst in the Krebs’ cycle [9]
- Increase energy production from the burning of pyruvic acid [9]
Nedostatek
- Deficiency of malic acid and fumaric acid is linked to chronic fatigue and psoriasis [9]
Supplementace
- Beneficial in Chronic Fatigue Syndrome by reducing symptoms of persistent fatigue, muscular myalgia and arthritic-like pains [9]
Malate dehydrogenase = malic enzyme
- Vzniká
- Oxalacetát (substr. pro citrát syntázu)
- Z NAD+ vzniká NADH+ a H+
Nezbytné kofaktory
Stimulována
- DHT alone stimulated the activities
- E2 alone failed in castrated animals.
- E2 + DHT stimulation and the response of the rhesus monkey´s epididymis [1]
- Estrogens in brain - zvedli syntézu [1]
Inhibována
- Alpha-ketoglutarate and citrate
- Allosterically inhibit malate dehydrogenase
- Dissociate this enzyme from the multienzyme system [13]
Oxalacetát
- Může také vzniknout z:
- Aspartate
Citrát syntáza
Nutné substráty
- Acetyl-CoA (z něho zbyde pak CaA-SH)
Citrát
- Může být transportován z MTCH do cytosolu, kde přeměny:
- ATP citrate lyase
- Z CoA, ATP, ADP+P1 vznik Acetyl-CoA
- Oxalacetate
- Malate dehydrogenase
- Z NADH vznikne NAD+
- Malate
- Malic enzyme
- Z NADP+ vznikne NADPH, a CO2
- Pyruvát
- Zpět transportován do MTCH
Literatura:
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[12] Alpha Ketoglutarate Dehydrogenase - Links Krebs Cycle to Amino Acid production - Everything2.com [Internet]. [citován 11. červen 2013]. Dostupné od: everything2.com/title/Alpha+Ketoglutarate+Dehydrogenase+-+Links+Krebs+Cycle+to+Amino+Acid+production
[13] Regulation of malate dehydrogenase activity by glutamate, citrate, alpha-ketoglutarate, and multienzyme interaction. [Internet]. [citován 11. červen 2013]. Dostupné od: www.jbc.org/content/263/22/10687.abstract
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