On Cellular Organization and Respiration
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ATP use:
- ATP + H₂O ⇉ ADP + Pi + H⁺
And 2 methods of regeneration:
'Substrate-level' phosphorylation:
- ADP + R-OP + *H⁺ → ATP + R-OH
(R for "Root")
Oxidative phosphorylation:
- ADP + Pi + H⁺ → ATP + H₂O
*Whether a H⁺ is consumed will depend on the reaction.
Creatine cycling does consume (→) and produce (←) H⁺:
- ADP + (Creatine-OP) + H⁺ ⇄ ATP + (Creatine-OH)
Throughout cellular respiration, it's tricky..
Enzyme Participants Dir. Participants HK ADP + R-OP + H⁺ ← ATP + R-OH PFK ADP + R-OP + H⁺ ← ATP + R-OH PGK ADP + R-OP + H⁺→ ATP + R-O⁻ PK ADP + R-OP + *H⁺→ ATP + R-O *But a hydrogen is incorporated elsewhere (R-CH₂ → R-CH₃):
We could argue that glycolysis metabolites become ionized as soon as phosphate is attached to them (early on in glycoylsis), and this contributes to their trapping in cells. However, the definite ionization occurs when phosphates start to be detached in PGK, where crapoxylates are formed (note in the table how H⁺ aren't consumed against expectation).
It's for the phosphorylation steps that you'll find a one-way arrow in diagrams, deeming them irreversible (except for PGK). However, if this was the case in all tissues, glucose resynthesis wouldn't be possible. As an example, the reactions of HK and PFK can be undone through phosphorylases that work as hydrolases:
- Glycolite-OP + H₂O → Glycolite-OH + Pi
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In oxidative phosphorylation, the PO₃⁺ (of inorganic phosphate; Pi) goes towards ADP, and OH⁻ (also from Pi) combines with H⁺ to form H₂O.
- ADP + Pi + H⁺ → ATP + H₂O
With substrate-level phosphorylation in mitochondria, we have a variation of it. SCS reaction (omitting the succinyl group):
- 'ADP' + Pi + CoAS⁻ → 'ATP' + CoASH
As before, the PO₃⁺ (of inorganic phosphate; Pi) goes towards ADP, but here OH⁻ doesn't combine with H⁺ to form H₂O. Rather, oxygen gets incorporated to yield succinate, and H⁺ is accepted by CoA instead of released immediately in free form. No additional H⁺ is consumed.
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Therefore, lactate formation aside, increase reliance on substrate-level phosphorylation for ATP resynthesis goes without the immediate compensatory H⁺ consumption, although complete metabolism should be an overall H⁺-consuming process.It's worth noting the complicators.
Free phosphates will occur as mixed species that take up more or less H⁺ depending on its concentration, and differences in acidity between compartments will affect the composition.
We also know that most of the ATP is produced in mitochondria and consumed in the cytosol. The synthesis of ATP with H⁺ consumption occurs in a more alkaline environment relative to where most of ATP is hydrolyzed. At some stage, the extra H⁺ taken up by phosphates in the cytosol will have to be released when the phosphates in question return to mitochondria. -
@Amazoniac Thanks!
It is on my reading list now! Main goal not to side-track
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Does Aerobic Respiration Produce Carbon Dioxide or Hydrogen Ion and Bicarbonate?
The majority of CO₂ in the body circulates as the hydrocarbonate ion:
Carbon dioxide and derivatives Content Hydrocarbonate ion (HCO₃⁻) ~70% Carbamates (protein-bound; R-NH-CO₂) ~23% Carbon dioxide (CO₂) ~7% Carbonic acid (H₂CO₃) <1% Organic anions are considered alkalinizing when they are hydrocarbonate precursors. However, prior to its formation, CO₂ has to be hydrated, and for every hydrocarbonate ion derived from CO₂, a H⁺ is released in the system:
- CO₂ + H₂O ⇄ H₂CO₃ ⇄ H⁺ + HCO₃⁻
The H⁺ are temporarily sequestered, but complexation doesn't negate it.
It's easy to overlook the H⁺ load for not being apparent in circulation, where normal levels are:
- [HCO₃⁻]: 22-32 mmol/L
- [H⁺]: 0.000036-0.000043 mmol/L (from pH: 7.44-7.37)
Far from a 1:1 ratio.
It can be argued that hydrocarbonate precursors alkalinize for consuming H⁺ in priming molecules for complete oxidation (into CO₂ and H₂O), which is true, but the consumption is compensated when the equivalent of carbonic acid molecules appear in the system.
Unlike non-volatile acids that can remain paired by a corresponding counter-ion until elimination (example: sodium sulfate), the occurrence of carbonic acid or variants yields CO₂ and H₂O. This CO₂ leaves the body, and the original pairing cation is left as unpaired as residue (example: sodium
citrate).To maintain ion neutrality and rebalance, the body may try to lower cations, which would affect H⁺ concentration, and conserve anions, including hydrocarbonate. Fluid redistribution from the excess cation can also dilute H⁺. The hydrocarbonate are first and foremost carbonic acid precursors, so we need explanations along these lines.
@Lejeboca said in On Cellular Organization and Respiration:
@Amazoniac Thanks!
It is on my reading list now! Main goal not to side-trackСпасибо за визит.
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Each turn of the TCA cycle eliminates 2 carbons in consecutive (oxidative) decrapoxylation steps:
- IDH: isocitrate → ketoglutarate* + CO₂
- KGDH: ketoglutarate* → succinyl(CoA) + CO₂
A peculiarity of the TCA cycle is that succinate and (its product) fumarate are symmetrical molecules (⇈). Since this property applies to both of them, we can tell that succinate dehydrogenase modifies succinate evenly.
The next reaction is the conversion of fumarate to malate, where asymmetry appears. Even though fumarate is symmetrical, it contains newer or older atoms throughout the molecule. Depending on which side of fumarate is primarily changed after fumarase, the carbon stay in the cycle will differ.
This gives an idea:
I've adapted it for ease of tracing and until completion:
Therefore, the original carbons (from a given acetyl group) aren't eliminated straight away. They remain intact on the 1st turn, and the chances of their complete elimination appear to be:
- 50% on the 3rd turn
- 25% on the 4th turn
- 12.5% on the 5th turn
- 6.25% on the 6th turn
- ...
*Ketoglutarates:
- 2-oxoglutarate = a-ketoglutarate
- 3-oxoglutarate = b-ketoglutarate
Alpha refers to the second carbon because the first is the crapoxyl group, that's disconsidered in counting (similar to beta-oxidation).
Urine Organic Acids as Potential Biomarkers for Autism-Spectrum Disorder in Chinese Children
"[..]3-oxoglutarate, a common metabolite of yeast and fungi (Thomas et al., 2010; MacFabe et al., 2011; Kocovska et al., 2012), was significantly lower in children with autism. The low concentrations of both carboxycitric acid and 3-oxoglutarate that we observed in urine from autistic patients could be due to increased uptake of these compounds across the blood-brain barrier of the brain. Our results are consistent with previous studies that showed anti-fungal treatments for children with autism can effectively reduce the amounts of corresponding organic acid indicators (Cobb and Cobb, 2010), and suggests that gastrointestinal yeast could provide a basis for dietary adjustments such as gluten/casein-free diets that are important for children’s nervous system development and could mitigate autism symptoms. 3-oxoglutarate in urine is associated with the presence of harmful gut flora such as Candida albicans (Schmidt, 1994)."
It's fine to omit the 'alpha' prefix from ketoglutarate for the same reason that we only need to clarify which Paris we're going to when it's not the one in France.
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At last, an objective comparison of dietary toxins:
Since these coenzymes are recycled, the most expensive phase with them must be in adapting to different needs. Once the cell becomes adapted, it's a matter of replenishing obligatory losses. I've omitted some coenzymes for clarity.
The comparison makes it clear once again that the oxidation of glucose doesn't produce more CO₂ per molecule metabolized than fatty acids.
What explains the CO₂ effect is a difference in ATP production: fatty acid oxidation can yield about 25% more ATP than glucose on a carbon basis (P/C), resulting in less exposure to CO₂ to produce the same energy.
The NAD/FAD ratios in their complete catabolism:
- NAD 5:1 FAD -- Glucose
- NAD 2:1 FAD -- Fatty acids (rounded for common ones)
Someone may associate FAD with Complex II and have with the impression that fatty acid oxidation overwhelms Complex II. However, if we match substrates for energy yield and argue that glucose oxidation exposes the person to more CO₂, we must be consistent with the matching in other comparisons.
We're dealing with different pools of FAD:
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FAD within the ACADH-ETF-ETFDH complex (more about it below) is responsible for the marked decrease in the NAD/FAD ratio;
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FAD within SDH (Complex II) remains similarly affected by glucose and fatty acids.
These are separate routes of transferring electrons.
With a focus on the first mentioned route, the middle row shows the 4 enzymes of a standard β-oxidation cycle:
Lack of Myoglobin Causes a Switch in Cardiac Substrate Selection
Abbreviation Enzyme Function ACADH Acyl-CoA dehydrogenase Oxidation ..and the Trifunctional Protein (TFP) set: ECH Enoyl-CoA hydratase Hydration HADH Hydroxyacyl-CoA dehydrogenase Oxidation KAT Ketoacyl-CoA thiolase Thiolysation The bottom row of the image shows the respiratory complexes.
In between the middle and bottom rows, linking β-oxidation to respiratory dehydrogenases, are the mobile ETF and NAD molecules.
- ACADH → ETF → ETFDH
- HADH → NAD → Complex I
ETF stands for Electron-transfer Flavoprotein, which is carrier molecule and the FAD equivalent in purpose to NAD.
ETFDH (ETF Dehydrogenase) is a respiratory complex that metabolizes ETF. It's sometimes called ETF:Q-O (ETF-to-Quinone Oxidoreductase).
FAD occurs embedded in ACADH, and the same applies to each of these interacting proteins:
- ACADH (FAD) → ETF (FAD) → ETFDH (FAD)
It's fad everywhere, resembling a thiamin overdose support group.
The paths of these β-oxidation dehydrogenases (ACADH and HADH) eventually converge in ubiquinone.
FAD-dependent NAD-dependent β-ox. Enzyme ACADH HADH Carrier ETF NAD Resp. Enzyme ETFDH (ETF:Q-O) Complex I (NADH:Q-O) Carrier ⤷ UQ ⤶ Resp. Enzyme Complex III Carrier Cyt c Resp. Enzyme Complex IV Therefore, the extra FAD cycled in fatty acid oxidation doesn't involve SDH (Complex II), but the ACADH-ETF-ETFDH complex featured above.
Since every acetyl-CoA that's metabolized in the TCA cycle is derived oxidatively from a β-oxidation cycle, we'll have a succinate (from TCA cycle → SDH) molecule for every ETF (from β-oxidation → ETFDH); so, the different routes distribute electrons somewhat evenly between them, without burdening Complex II.
⠀Source: the internet, but possibly Albie's Principles of Biochemistry.
It's an almost even distribution because the last acetyl-CoA isn't derived oxidatively, but as a leftover product of the final β-oxidation cycle, which explains one less FAD needed in ACAD/ETF/ETFDH (check the original tables).
As a side note, the catabolism of certain amino acids and choline is also dependent on ETF-ETFDH.
Electron transfer flavoprotein and its role in mitochondrial energy metabolism in health and disease
Along the lines of taking energy into account, the ratio of ATP produced to oxygen consumed (P/O) indicates how fatty acid reliance needs less oxidation than anticipated, it's not too far behind glucose.
In addition, the components related to β-oxidation can cluster with the respiratory complexes to maximize efficiency and minimize damage. 'Respirasome' (CI + CIII₂ + CIV) is a known respiratory supercomplex, but we also have lesser-known associations, one of them coordinating ETFDH with CIII, while ACADH and ETF likely remain nearby.
"For steps 1–3, long-chain acyl-CoA substrates are transferred into mitochondria as acylcarnitines, which cross from the intermembrane space into VLCAD through CPTII in the inner membrane. VLCAD then accepts and catalyzes the released long-chain acyl-CoA substrate to its enoyl–CoA product with reduction of ETF. The protein complex promotes metabolite channeling for all these reactions.
For steps 4 and 5, reduced ETF is released from VLCAD into the mitochondrial matrix, where it is free to find its redox partner, ETFDH, and shuttle its reducing equivalents (QH2) to ETC complex III. Alternatively, for high catalytic efficiency of transfer of electrons from FAO to ETC, the ETF may remain associated with the macromolecular FAO–ETC complex and instead slide down the membrane-associated proteins to more efficiently contact ETFDH.
For steps 6 and 7, long-chain enoyl–CoAs, from VLCAD, channel directly to TFP where the next three reactions in the cycle occur, producing one molecule of acetyl-CoA and an acyl-CoA substrate that is two carbons shorter. As the acyl-CoAs become shorter, they become more hydrophilic, allowing them to be released into the matrix. NADH generated by the LCHAD reaction of TFP can directly channel to the NADH-binding domain of complex I.
For step 8, in complex I NADH is oxidized through iron–sulfur clusters to generate QH2 at the Q-binding domain, which is then transported through the membrane electron channel of complex I to complex III.
For steps 9 and 10, medium- and short-chain acyl-CoA substrates produced by TFP are transferred to MCAD and SCAD in the matrix or in a more weakly-associating peripheral domain of the multifunctional FAO–ETC complex. ETF is once again reduced and released to ETFDH, as in step 5. The remaining FAO reactions are catalyzed by monofunctional enzymes that are likely also weakly associated at the periphery of the complex.
For step 11, ETFDH oxidizes reduced ETF by reducing CoQ to QH2, which is then channeled to ETC complex III.
Finally, the acetyl-CoA generated by FAO is free to enter the TCA cycle or to be utilized for ketone body production (steps 12 and 13)."
For an overview:
If the cell starts to rely more on fatty acid oxidation and there is an excess of ubiquinol relative to Complex I use, electrons can flow back, leading to the formation of 'reactive oxygen species' and a purposeful disintegration of Complex I. This frees the associated Complex III to reorganize supercomplexes in a way that meets a different demand. Therefore, where fatty acid oxidation is dangerous, the body tries to regulate it as drugs.
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And an incomplete list of unexpected CO₂ sources:
Process Enzyme Reaction Pentose Phosphate Pathway PGDH Hexose (6C) → pentose (5C) + CO₂ (1C) Fatty acid synthesis KAS* Malonyl (3C) + acetyl (2C) → ketobutyryl (4C) + CO₂ (1C) Acetone synthesis - Acetoacetate (4C) → acetone (3C) + CO₂ (1C) Oxoglutarate oxygenases OGO Oxoglutarate (5C) → succinate (4C) + CO₂ (1C) Pyruvate synthesis from malate ME Malate (4C) → pyruvate (3C) + CO₂ (1C) PEP synthesis PEPCK Oxaloacetate (4C) → pyruvate-enol-phosphate (3C) + CO₂ (1C) Glycine cleavage system GLDC Glycine (2C) + THF (+0C) →→ methylene-THF (+1C) + CO₂ (1C) Coenzime A synthesis PPCD PPC (12C) → P4P (11C) + CO₂ (1C) Aldehyde dehydrogenase ALDH formyl-THF (+1C) → THF (+0C) + CO₂ (1C) Taurine synthesis CSAD CSA/CA (3C) → hTau/Tau (2C) + CO₂ (1C) Cholesterol synthesis PPMD Mevalonate-5-diphosphate (6C) → Isopentenyl diphosphate (5C) + CO₂ (1C) Polyamine synthesis SAMD SAM (–0C) → dcSAM (–1C) + CO₂ (1C) Other biogenic amine syntheses (AA decarboxylations) † *Preceded by carbon incorporation: gain followed by loss. But remains a reaction that releases carbon dioxide.
†Biochemical and Pharmacological Properties of Biogenic Amines
