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Tensegrity #8, Insulin Sensitivity, Molybdenum, Ubiquitin Pathways

Discussion in 'The Cave' started by yewwei.tan, Nov 7, 2014.

  1. yewwei.tan

    yewwei.tan Gold

    This is a long read. Furthermore, it is just my speculative thoughts trying to link together concepts after listening to the November 2014 Webinar and reading Tensegrity #8.

    I tried to make it coherent, but reader beware. :eek:

    ----

    Personal MCT oil issues

    I had massive issues with Coconut Oil consumption back in Melbourne. Nausea, brain fog, etc ... Taking Molybdenum improved that.

    I first wrote about the symptoms here -- http://forum.jackkruse.com/index.php?threads/take-it-slow.9428/page-3#post-111338

    Josh made the suggestion to take Molybdenum back in Feb 2014 -- http://forum.jackkruse.com/index.php?threads/take-it-slow.9428/page-4#post-111454

    2 week update after Molybdenum supplementation (asymptomatic after MCT oil) -- http://forum.jackkruse.com/index.php?threads/take-it-slow.9428/page-5#post-115735

    Now that I'm in Cairns, I don't need to take Molybdenum to handle fats anymore.

    ----
    FADH2:NADH Ratios

    Peter on Hyperlipid talked about this ratio in this post -- http://high-fat-nutrition.blogspot.com/2012/08/protons-fadh2nadh-ratios-and-mufa.html

    Key quotes:

    Each cycle of beta oxidation (assuming an even numbered carbon chain fully saturated fatty acid) produces one FADH2, one NADH and one acetyl-CoA. This gives a total of 2FADH2 inputs and 4 NADHs per cycle of beta oxidation.

    The very last pair of carbon atoms in a saturated fat do not need to go through beta oxidation as they already comprise acetate attached to CoA, so they can simply enter the TCA as acetyl-CoA. This last step only produces 1 FADH2 and 3 NADHs, with no extras.

    The shorter the fatty acid, the less FADH2 per unit NADH it produces. Short chain fatty acids like C4 butyric acid have an F:N ratio of 0.43 while very long chain fatty acids, up at 26 carbons, have an F:N ratio of about 0.49.

    The F:N ratio of C8 is about 0.47, a value chosen by metabolism as the end product of peroxisomal shortening

    Very long chain fatty acids end up in peroxisomes for shortening, usually to C8, which is then shunted to mitochondria for routine beta oxidation.

    Of course peroxisomal beta oxidation generates zero FADH2, except that from acetyl-CoA, because peroxisomal FADH2 is reacted directly with oxygen to give H2O2. And heat, of course (TYW: this must be significant, but I have no clue of the mechanism for now)

    The ratio of F:N generated by a metabolic fuel sets the ability to generate reverse electron flow through complex I and subsequent superoxide production, macroscopically described as insulin resistance.

    An F:N of 0.47 is not a serious generator of superoxide and an F:N of 0.48 is.

    ----

    Another quote from Peter: http://high-fat-nutrition.blogspot.com/2012/10/protons-love-your-superoxide-outside.html

    No fatty acids. No glycerol 3 phosphate. No FADH2 input to the CoQ couple. No free radicals. No signal for mitochondrial biogenesis. No mitochondrial biogenesis.
    More big links by Jack (comments section) in this post from Peter: http://high-fat-nutrition.blogspot.com/2014/10/where-has-superoxide-gone.html

    Superoxide production is tied to the electric current size and the resultant magnetic force generated from the current.

    Peter is pulling the veil back on how a low superoxide level is a proxy for ECT current changes and the polarity of magnetic flux at the 5th cytochrome: The ATPase.

    I would also remind you that the the ATPase has a Fo rotating head that also acts to the action of both ECT forces and the associated magnetic flux.

    One other point I'd like to make regarding superoxide is how it is made by sunlight on the skin. When UVB sunlight is missing cholesterol can not be sulfated in the skin and superoxide also drops like a rock in the skin

    When superoxide drops, magnetic flux in the mitochondria are also destroyed leaving cholesterol in the blood too long allowing it to become oxidized. Sunlight makes cholesterol more water soluble in blood to go where the mitochondria need it to be.

    When you understand 3 D molecular dynamics, superoxide is a fundamental signaling molecule where transition metals and sulfur exist (TYW: molybdenum link). This happens in the skin and the cytochromes. Superoxide is actually needed to oxidize sulfur to make sulfated versions of proteins​

    **Important Sidenote**: Nick Lane is referenced many times regarding this topic. He was mentioned again in the Nov2014 Webinar. I have yet to read his works.

    ---

    ItsTheWooo has talked about how MCTs (which again, have that 0.47 F:N ratio) can be insulin tropic under certain conditions: http://itsthewooo.blogspot.com/2014/08/keto-salts-mct-perhaps-useful-during.html#more

    MCT are insulin tropic, can induce hypoglycemia greater than contribution of ketones.

    At least this is likely true in people who are dramatically weight reduced with insulin sensitive adipose and sympathetic/adrenergic deficits at site of adipose such as myself.

    In people without a significant risk/history of obesity the insulin stimulating effect of MCT is likely much too weak to shift blood nutrients or suppress lipolysis. In my case though it can definitely induce hypoglycemia on occasion if I take too much coconut oil for example​


    Ha, this describes a likely mechanism for my issues I described above. My immediate thought was: Insulin sensitivity is just another way of saying that you have a suppressed superoxide generation response.

    Why would Molybdenum fix this issue somewhat as it did it me? Well, I found this paper on rats -- http://europepmc.org/abstract/med/1632832 . 'Synergism in insulin-like effects of molybdate plus H2O2 or tungstate plus H2O2 on glucose transport by isolated rat adipocytes'

    Molybdate is exactly the Mo6+ ion that Jack talked about in the Nov2014 Webinar and Tensegrity #8.

    Abstract:

    The effect of molybdate, tungstate, molybdate plus H2O2 or tungstate plus H2O2 on 3-O-methylglucose (3-O-MG) uptake was studied in isolated rat adipocytes to investigate whether these agents possess an insulin-like action.

    High concentrations (10-30 mM) of molybdate or tungstate significantly stimulated the uptake of 3-O-MG while 1 mM of the metaloxides did not.

    The combination of 1 mM molybdate and 1 mM H2O2, or 1 mM tungstate and 1 mM H2O2 induced striking stimulation of the uptake of 3-O-MG in a synergistic manner, whereas 1 mM H2O2 alone showed only a small effect.

    The effect of metaloxides plus H2O2 (1 mM) and the effect of insulin (20 nM) were not additive, and both effects were ATP or energy dependent based on experiments using KCN.

    These results indicate that a weak insulin-like effect of molybdate or tungstate is potentiated synergistically with H2O2, presumably by producing peroxocompounds. Based on the present findings, these new agents may be useful for investigating the mechanism of insulin action and may indicate a new class of drugs for diabetes mellitus.

    Another paper -- http://link.springer.com/article/10.1007/s10967-011-1565-1 . 'Studies on dynamic dissociation constant of 99Mo–insulin complex'. Again, this references Mo6+

    insulin may act as good carrier of 99Mo to the intestine and may be useful in the field of nuclear medicine.


    My conclusion was that Molybdenum regulates the contribution and negative feedback cycles of electrons derived from Fatty Acid oxidation. It's function as an electron sink is to buffer excess electrons if need be.


    -----
    On to Insulin

    I recently speculated on the role of Insulin as a "cellular un-condenser" in my log, along with thoughts about protein intake, and protein recycling via the Ubiquitin Pathways (Long read o_O):
    Key quotes from those posts:

    I suspect that one of the key functions of dietary protein is to un-condense/un-fold our own proteins through the addition of protons for cellular signalling to occur. Insulin is just another "cellular un-condenser".

    The corollary is that excess dietary protein basically pushes excess positive charge to your proteins, and excess positive charge leads to the over-active ubiquitin cycle expression that I experience only 1-2 days post exercise.


    What does protein breakdown to? Nitrogen. My immediate thought was that absent sufficient electrons, excess protein gets you lots of Reactive Nitrogen Species. (nitrogen gets oxidised => electrons are taken away from it)

    Given the latest blog, this must link up with Molybdenum somehow. Does Molybdenum allow you to "deal with excess protein"?


    This was also written right now some basic reading of the Unfolded Protein Response, and how insulin stimulates that -- http://en.wikipedia.org/wiki/Unfolded_protein_response

    I have many initial thoughts about how this ties to Ubiquitin, exercise, PGC-alpha stimulation, calcium efflux, and ultimately cellular apotosis, but I think I'll leave that for another post :p

    =====

    If you've made it through this post, I'd definitely want to discuss these topics further :D to clear up my misconceptions (which I definitely have).



    .
     
    Last edited: Nov 7, 2014
    Martin, Optimalbound, kovita and 4 others like this.
  2. Jack Kruse

    Jack Kruse Administrator

    BOOM........you are front of the class.
     
    Josh likes this.
  3. yewwei.tan

    yewwei.tan Gold

    Calculating FADH2:NADH ratios

    I didn't see this anywhere, and Peter's posts isn't exactly that straightforward either :confused:

    So here's how you calculate the ratio:
    • Divide the number of carbons by 2. Call this number c
    • let d be the number of double bonds
    • If fully saturated
      • Let n = c - d - 1
      • (FADH2) F = 2n + d
      • (NADH) N = 4n + 3(d + 1)
    • if at least 1 double bond
      • Let n = c - d
      • F = 2n
      • N = 4(c - 1) + 3
    • Final_Ratio = (F / N)
    eg: Palmittic acid, which is 16:0 (16 carbons, 0 double bonds)

    c = 16 / 2 = 8
    d = 0
    n = 8 - 0 - 1 = 7
    F = 14 + 1 = 15
    N = 4*7 + 3*(0 + 1) = 31
    Ratio = 15 / 31 = 0.4839

    eg 1: Palmitoleic. 16:1 (16 carbons, 1 double bond)

    c = 16 / 2 = 8
    d = 1
    n = 8 - 1 = 7
    F = 2*7 = 14
    N = 4*(8 - 1) + 3 = 31
    Ratio = 14 / 31 = 0.4516
    Those should yield the corresponding values given above.

    An example of Oleic Acid (80+% of olive oil) which is 18:1

    c = 9
    d = 1
    n = 8
    F = 16
    N = 35
    Ratio = 0.45714 (slightly higher than Palmitoleic, showing increasing FADH2:NADH ratio with increasing chain length)
    An example of Linoleic Acid, which is 18:2 (polyunsaturated omega 6 fat which most of the time you should avoid in large quantities)

    c = 9
    d = 2
    n = 7
    F = 14
    N = 35
    Ratio = 0.4 (showing that greater unsaturation lowers the ratio)​

    Unsaturated fats are more insulin sensitising, and lack the superoxide burst needed for cellular signalling.

    ALA (alpha linolenic acid), your so-called "vegetable based omega 3", is highly insulin sensitising. If I remember correctly, Tim Ferriss has speculated (in one of his 'Tim Ferriss Show' podcasts) that Seth Roberts, a proponent of some ALA supplementation, died due an error in dosing ALA.

    ----

    List of saturated fats -- http://en.wikipedia.org/wiki/List_of_saturated_fatty_acids
    List of unsaturated fats -- http://en.wikipedia.org/wiki/List_of_unsaturated_fatty_acids

    Note: You will notice that the formula assumes an even number of Carbon atoms. There are basically no odd-numbered-carbon Unsaturated fats. There are many odd-numbered-carbon Saturated fats, but they either don't occur naturally, or appear in miniscule amounts. There must be an explanation for this o_O

    Note: the FADH2:NADH ratio doesn't apply to DHA (22:6) because it isn't used for energy, and never enters the ECT
     
    Josh likes this.
  4. Jack Kruse

    Jack Kruse Administrator

    The explanation is called fractal design.
     
  5. Josh

    Josh Gold

    Yew, you make my aging head spin....

    I am considering:
    1. what about the function distorting effects of nnEMF on transition metals such as Mo?
    2. Is it mostly an E=MC2 issue with loss of mass equivalence and cellular signalling?
    3. Or, does it alter the spin of the electrons and coherence as well for example?
    4. What are the symmetry issues with S and Mo?
    5. the quantum level "dance" in the methylation cycles that is obscured by the complex biochemical explanations.
     
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  6. Jack Kruse

    Jack Kruse Administrator

    The distorting effects are where metabolic syndrome comes from Josh...........It is due to relativity effect of the D shell electrons of Mo.
     
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  7. kovita

    kovita Gold

    too bad i can't stand as a valid discussion partner here for you! As always precise and analytical. there are some hints for my own story, I save them on my list and follow the brain storm of senior members ;-)
     
  8. Da-mo

    Da-mo Gold

  9. yewwei.tan

    yewwei.tan Gold

    Random thoughts early this morning while in the ocean (yay for electrons :p)
    Seasonality of Fats

    While I mentioned that I had issues with coconut oil and MCT, these issues were more pronounced in the winter time. At the time, Jack just told me that there is a seasonality to fats, which was laid out pretty well in Brain Gut 6 -- http://jackkruse.com/brain-gut-6-epi-paleo-rx/

    The FADH2:NADH ratio is basically a numeric representation of which fats are suitable for the season. The amount of superoxide signalling required in each season is going to be different, and thus the type of fat consumed should generate the appropriate level of superoxide.

    This is probably more important in winter time, when fats predominate the diet, and thus are the largest dietary contributor to superoxide production (though I'd argue that this is probably important year-round in this high nnEMF world).

    Summer time is probably when you want to be "more inflammed", which is another way of saying "more fertile", "more insulin sensitive", "have proteins that are less condensed", which in my mind, is just a general way of saying that you are more sensitive to the environment in summer time.

    It is also my opinion that in the original evolutionary context, you didn't need fat to provide for superoxide signalling during summer time. You ate carbs to get superoxide. The fats that naturally occurred at this time should promote insulin sensitivity to allow one to "better utilise carbs". These fats would be the PUFAs -- anything below the 0.47 FADH2:NADH ratio.

    ----
    "Coconut Oil is Fine Year Round for the Sick Person"

    The Epi-paleo Rx does not recommend coconut oil year round, likely for the reasons I just gave in the last section.

    The exception is coconut oil when you are sick. In other words, your cell signalling is poor, and you cannot respond well to changes in cell oxidation levels. Superoxide as a signalling agent loses a lot of its effectiveness in this case.

    The MCTs in coconut oil however, fall exactly in the 0.47 F:N ratio. Peter on Hyperlipid explained that a fat at this ratio generates some superoxide, and is a good target for beta oxidation.

    It feels like this 0.47 ratio generates just enough superoxide to tell a cell, "Hey! Pay attention to your oxidation state!", but doesn't blare that signal too loudly as to overwhelm the cell (and send it straight to apoptosis). Furthermore, these fats go to complex II for beta oxidation and produce good amounts of ATP for protein unfolding and energy generation from EZ water. Seems like a good plan to recover an unhealthy cell.

    Then there's also the benefits of the BHB produced, which Jack has talked about elsewhere (also in the threads about Nuts and butyrate production)

    ----
    Monounsaturated Fats with Seafood

    The fatty acid you will find in most high monounsaturated fatty acid (MUFA) sources is Oleic Acid (18:1) -- http://en.wikipedia.org/wiki/Oleic_acid

    (As usual, the figures below are from generic USDA food data. You may be able to get better quality fats)

    Now my question: Why does the Epi-paleo Rx recommend MUFAs to be eaten with seafood given that the most common MUFAs naturally available are slightly insulin sensitising?

    Again, what does "insulin sensitive" actually mean? Does this even have importance interactions with seafood?

    My guess is yes. And that "insulin sensitising" means an addition of electrons (usually only temporarily) to make a molecule/cell/tissue more paramagnetic. A paramagnetic molecule becomes a "nutrient sink". Whether or not you want something to be a collector of charged particles depends on the context, but in the case of the nutrients in seafood like DHA, iodine, etc ... having an insulin sensitising MUFA as an electron affinity enhancer would allow cells to better uptake these nutrients.

    Relative cell membrane fluidity will likely dictate that MUFAs attempt to fill the cells with the most rigid cell membranes first, making this a great carrier to deliver DHA to the cells that "need it the most". (I have no mechanism to explain this thought BTW, it's just a hunch :p)

    The transient insulin sensitising effect likely does not affect superoxide signalling regardless of the season. Still, MUFAs should probably NOT dominate your fat intake in winter time ... substitute the olive oil for butter :D

    .
     
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  10. BTA

    BTA New Member

    According to Chinese cosmology, winter will officially begin November 7, 2014.


    Winter is the season represented by the Water element. Water symbolizes darkness, mystery, wisdom, and rejuvenation. From the Daoist perspective, Water is the primary element - the place from which all life energy begins. For these reasons, winter is the time for recharging our vital Qi and is the best season for our internal cultivation practice.
    Dong Ling Jin Bu

    Qigong practice, sour, pungent and bitter flavored foods will help support your good health and strong Qi during this winter season.
     
  11. Jack Kruse

    Jack Kruse Administrator

    MUFA have one thing that is not fat related. Polyphenols.......and this acts on mTOR and ubiquination. Total change up reason why.
     
    Last edited: Mar 2, 2015
  12. Jack Kruse

    Jack Kruse Administrator

    Summertime is the time of more uncondensation of protein polymers, but you'd be wise to see why saturated fats (spins) are summertime oils. They totally fixate the cytoskeleton and limit the amount of un-condensing that can happen because of the summertime effect of light, glucose, and insulin. Here you begin to see the thermodynamic story unfold yet again. Size and shape of cells and mitochondria are the key metrics no one realizes, and I am pointing out in OSF and Tensegrity series totally trumps genetic expression in most cases. Soon you'll hear about the Peto paradox and Kleiber's law yet again and realize why large animals get less cancer and those that are smaller seem to be more at risk.......it is a "quantum thermodynamic" reason. It is an energy reason, not a genetic one. The proof that I am right has already been published.....in 1936 and again in 2012. George Halder in Nature Reviews Molecular Cell Biology Vol 13 pg 591-600. Maybe Stella can post the article here. I do not have it on this computer. This paper links collagen's piezoelectric current via integrin's to the cells actin and proton cabling....proton size and shape are key......which link it to the nucleus by the blueberry ball proteins called YAP/TAZ. This reply is a post into the future of the blog........Yew is stretching the canvas. Better questions lead to transforming thoughts.
     
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  13. yewwei.tan

    yewwei.tan Gold

    If something in the body is fractal, that means that there must be a more macroscopic self-similar system that exhibits the same sort of behaviour. Starting my search now ....

    Ha, I don't think I can be considered a senior member :p

    Any addition to the discussion is always valuable. It's always about asking better questions. The simple questions often are the ones that lie somewhere in a blind spot that we aren't able to see.


    A spinning (Fo) head isn't one that is aging :cool:

    Just going to write some initial random thoughts for now:

    I speculated about bacteria in the 'Fasted State Training Adaptations' thread, saying that they were "not as sensitive to nnEMF". Got an affirmative from Jack -- http://forum.jackkruse.com/index.ph...-training-adaptations.297/page-31#post-144225

    Bearing Tensegrity #8 in mind. The one thing that stood out was how heavy Molybdenum was. I first thought that heavy => harder to move around (by nnEMF) => harder to disrupt.

    Another thing was that the Molybdate ion [MoO4]2- is very soluble in water. Meaning it is easy to move around in the body, while not being as affected by the direct effect of nnEMF (unless of course nnEMF causes Ca2+ efflux or addition of other ionic chaotropes into the body's water)

    Still don't know what the quantum relationship between a group n and a group (n+10) on the periodic table is. (Molybdenum is in group 6 and Sulfur in group 16).​


    Also, I don't know why I missed it until now, but the original idea of Molybdenum allowing for nitrogenase enzymes should also mean that we retain the ability to perform "nitrogen fixing" within our body as well.

    I came across this paper 'Biosynthesis of the Iron-Molybdenum Cofactor of Nitrogenase' . Weeeee, connections were made o_O:cool: -- http://www.annualreviews.org/doi/full/10.1146/annurev.micro.62.081307.162737

    Quotes (bolded parts are my emphasis, underlined parts in square brackets are my notes):


    FeMo-co is required by the molybdenum nitrogenase to perform the chemically difficult lysis of the N2 triple bond (reviewed in Reference 39).

    FeMo-co is composed of an inorganic Mo-Fe7-S9-X portion and the organic acid R-homocitrate, which is coordinated by its C-2 carboxyl and hydroxyl groups to the Mo atom (Figure 2)

    The inorganic part of FeMo-co is regarded as one of the most complex iron-sulfur (plus a heterometal) clusters found in biology

    The molybdenum nitrogenase enzyme complex has two component proteins (10) encoded by the nifDK and the nifH genes.

    The NifDK component is a heterotetrameric (α2β2) protein formed by two αβ dimers related by a twofold symmetry (Figure 1)

    The P-cluster, also located beneath the protein surface, is coordinated by three cysteine residues from the NifD subunit and three cysteine residues from the NifK subunit.

    Electrons are transferred from the P-clusters to the FeMo-co embedded within the NifD subunits where reduction of substrates takes place (Figure 1).

    In the absence of N2, proton reduction activity is maximal, as more electrons are allocated to this process. However, a minimal 2:1 ratio of proton to N2 reduction is obligate even at high N2 pressure (76), indicating that proton reduction is an intrinsic part of the mechanism of N2 reduction.

    Figure 4 illustrates a schematic summary of our current model for FeMo-co biosynthesis. [give this image a look! -- http://www.annualreviews.org/na101/...737/production/images/medium/mi620093.f4.gif]

    This scheme has been centered on NifEN, a scaffold protein that is proposed to function as a central node in the pathway to which [Fe-S]-containing FeMo-co precursors, molybdenum and homocitrate, might converge to complete the assembly of FeMo-co

    Molybdenum is specifically donated by NifQ. The iron-sulfur core is provided by the sequential activities of NifS, NifU, and NifB. The cysteine desulfurase NifS directs the assembly on NifU of simple Fe-S clusters (probably [Fe2-S2] or [Fe4-S4]) that will serve as metabolic substrates for NifB-cofactor synthesis.

    NifB-co comprises the Fe6-S9 core of FeMo-co (26) but lacks molybdenum and homocitrate (72). NifX would mobilize NifB-co from NifB to NifEN (32).

    Although we hypothesize that the molybdenum, iron-sulfur, and homocitrate precursors converge on NifEN, it is not clear whether NifEN alone provides a homocitrate binding site.

    Current evidence indicates that both NifEN and NifH must be present to achieve homocitrate incorporation into the FeMo-co precursor.

    Finally, assembled FeMo-co would be transferred to apo-NifDK via NafY, the product of a non-nif gene that also stabilizes the target apo-NifDK protein

    [Note: cysteine and homocysteine have both S and N. When "desulfurase" is mentioned, it means the sulfur has been donated (to iron in this case it seems)]

    A series of elegant studies in the laboratories of Dean and Johnson demonstrated that NifU and NifS compose cellular machinery for the assembly of [Fe2-S2] and [Fe4-S4] clusters under nitrogen-fixing conditions (reviewed in Reference 45). NifS is a cysteine desulfurase that provides sulfur for the assembly of transient [Fe-S] clusters onto the molecular scaffold NifU

    It was also shown that NifU and NifS were nitrogenase-specific homologs of the IscU and IscS proteins (85), which are involved in general [Fe-S] cluster assembly in a wide range of organisms

    -----
    Continued in next post o_O
     
  14. yewwei.tan

    yewwei.tan Gold

    Continued from previous post ....


    NifU comprises three well-defined highly conserved domains, all of which have the ability to coordinate an [Fe-S] cluster. The second (middle) domain carries four conserved cysteines that coordinate one [Fe2-S2] cluster

    NifU and NifS are also involved in the assembly of the P-cluster and theFeMo-co of the NifDK component of nitrogenase

    The synthesis of each P-cluster has been proposed to occur in two steps:
    (a) formation of two [Fe4-S4] cluster units at the interface of the NifD and NifK subunits, and
    (b) NifH-dependent condensation of these clusters to generate the mature [Fe8-S7] P-cluster

    According to its primary sequence, the N-terminal domain of NifB belongs to the SAM radical protein family (79). SAM radical proteins contain an [Fe4-S4] cluster coordinated by three cysteine residues and a molecule of SAM [I think I heard SAMe mentioned somewhere on the blog, can't seem to find it now o_O]

    NifB seems to be a molecular scaffold for the assembly of NifB-co. As isolated from A. vinelandiicells, NifB did not support in vitro FeMo-co synthesis. However, incubation of purified NifB with ferrous iron, sulfide, and SAM under reducing conditions resulted in the incorporation of additional [Fe-S] clusters into NifB, which acquired the ability to substitute for NifB-co and support in vitro FeMo-co synthesis

    The properties of NifB, including its ability to readily support FeMo-co synthesis, were different when purified from K. pneumoniae or from A. vinelandii cells. The enzyme isolated from K. pneumoniae contained more iron and readily substituted for NifB-co in the in vitro FeMo-co synthesis assay without a requirement for iron, sulfide, or SAM

    NifQ proteins have a conserved Cx4Cx2Cx5C amino acid motif that was proposed to be a binding site for an [Fe-S] cluster, a molybdenum-containing metal cluster, or a Mo-S intermediate for FeMo-co synthesis

    Because the phenotype of nifQ mutants is leaky, and because molybdate satisfies the molybdenum requirement for FeMo-co synthesis in vitro, the determination of a physiological provider of molybdenum for FeMo-co biosynthesis has been elusive. High concentrations of molybdate (41) or cysteine (81) (the sulfur source for [Fe-S] cluster biosynthesis) in the growth medium can suppress the nifQ phenotype. This was originally interpreted as an indication that a nonenzymatic reaction between molybdenum and sulfur could substitute for the reaction catalyzed by NifQ [TYW: hahaha, EMF at work again :p, and I don't understand what exactly this is yet again :rolleyes:]

    NifQ is an iron-sulfur protein with a redox-responsive [Fe-S] cluster. NifQ is also a molybdoprotein that serves as a direct molybdenum donor for FeMo-co synthesis, replacing molybdate in the in vitro FeMo-co synthesis assay

    NifQ was unable to donate molybdenum for FeMo-co synthesis unless NifH and NifEN were simultaneously present in the reaction. One possible interpretation is that molybdenum delivery proceeds from NifQ to a NifEN/NifH complex.

    99Mo-radiolabeling experiments have indicated that addition of molybdenum to the [Fe-S] core of FeMo-co precedes homocitrate incorporation (57). It is not known by which mechanism homocitrate is coordinated to molybdenum and how the FeMo-co synthesis machinery discriminates against other organic acids present in the cell. There is a mechanism for homocitrate incorporation in vivo that appears to be specific enough to discriminate against similar organic acids that are not incorporated into FeMo-co.

    The site of homocitrate incorporation into the cofactor is also a matter of debate. [TYW: or maybe, the site differs based on protein folding, which is based upon the electric and magnetic environment of the protein :rolleyes:]

    An interesting characteristic of NifEN is the lability of some of its [Fe-S] clusters, which are lost during the purification of the protein, yielding NifEN preparations with different [Fe-S] cluster content.

    At least three reactions of the FeMo-co biosynthetic pathway have been proposed to occur within NifEN:
    • incorporation of additional iron
    • insertion of molybdenum
    • incorporation of homocitrate.
    The first reaction entails the conversion of NifB-co into the VK-cluster. Like NifB-co, the VK-cluster does not contain molybdenum or homocitrate.

    However, NifB-co and the VK-cluster are electronically different because NifB-co is EPR silent and the VK-cluster shows EPR signals in the reduced and oxidized states. Two lines of evidence suggest that additional iron atoms are added to NifB-co to convert it to the VK-cluster:

    • (a) When NifDK protein was matured in a NifB-co-dependent FeMo-co synthesis and insertion assay in the presence of additional 55FeCl3, it incorporated some 55Fe label, suggesting additional incorporation of iron after the stage of NifB-co (16).
    • (b) A comparison of EXAFS data from isolated NifB-co and isolated VK-cluster shows differences that favor a six-iron-atom structure for NifB-co (26) and a seven- (or eight-) iron-atom structure for the VK-cluster
    The second reaction that takes place within NifEN is the incorporation of molybdenum into the FeMo-co precursor, which appears to occur in two steps. Initially, molybdenum is incorporated into a transient site on NifEN.

    Subsequently, molybdenum is mobilized into the VK-cluster-derived FeMo-co precursor in a reaction that requires NifH and Mg⋅ ATP (36, 38, 57). Reports on whether ATP hydrolysis is required at this step are contradictory. Although there is indirect evidence that NifEN might bind Mg⋅ ATP, no ATP hydrolysis activity was detected in purified NifEN (56) and the attention was turned to the ATP-hydrolyzing protein NifH

    [TYW: maybe what is needed is just any Electron Withdrawing Cardinal Adsorbent (EWC)]

    The third reaction would be the incorporation of homocitrate into the precursor to generate FeMo-co, which is thought to be NifH dependent. This proposal is speculative because the binding of homocitrate (e.g.,14C-homocitrate) to NifEN has not been demonstrated, and the processing of homocitrate in vitro requires the presence of other substrates (the VK-cluster and molybdenum) and proteins (NifH). It is not clear whether incorporation of homocitrate directly requires NifH

    NifX and NafY are members of a family of nitrogenase cofactor binding proteins that would additionally include NifY, the C-terminal domain of NifB, and the VnfX and VnfY proteins (involved in assembly of iron-vanadium cofactor (FeV-co) for the vanadium nitrogenase)

    [TYW: oh boy, now we need to look at vanadium too!]


    That quick excerpt doesn't cover everything in the research paper. But it's pretty clear that Molybdenum is involved in binding and releasing Sulfur, and both interact to form compounds which can modulate levels of Nitrogen in the body.

    Iron-Sulfur clusters have been mentioned on this forum and the blog multiple times. They are important, but I'll leave that for another post .... after I let this information sit in my head for a couple days ....
     
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  15. yewwei.tan

    yewwei.tan Gold

    Add another list of reasons for there to be a functional cell membrane then :). -- You can get localised and controlled protein polymer uncondensation without affecting the entire system.

    What's the purpose of trying to uncondense our own protein polyers anyway? Isn't it just to make them more sensitive to the electromagnetic and electrostatic force to accurately sense the environment, as well as to provide more energy (EZ water binding sites) to adapt to the newly sensed changes?

    If so, is then a large, more energy inefficient cell/body (remember scale independence) more capable of responding to environmental cues?

    Does a larger body imply a higher water to protein ratio?

    My current understanding is that cancer is a choice made by the cell when energy cannot be provided fast enough. But what are we providing the energy for? Not enough energy for what process exactly?

    What about O2 transport? Tensegrity #7 and #8 keeps mentioning O2 transportation being dangerous without Sulfates and Nitrates. Both of those are provided by proteins right?

    ----

    Time to sit on the beach with more questions :confused:
     
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  16. Sat fats = rigid cell membrane, n3 PUFA cell membrane = flexible

    i always saw the uncondensed matter thing as a response to best open the system to as much info as possible
    this is likely why the leaky gut happens in a stress response situation...i think that was in a blog somewhere
     
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  17. Jack Kruse

    Jack Kruse Administrator

    yep...........lots of stuff i drop in blogs like that
     
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  18. nonchalant

    nonchalant Silver

    What's up with @yewwei.tan anyway? He moves to a new place, and he becomes even more awesome.
     
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  19. av8r

    av8r New Member

    “but you'd be wise to see why saturated fats are summer time oils.”

    “Size and shape for cells and mitochondria are the key metric no one realizes, and I am pointing out in OSF and Tensegrity series totally trumps genetic expression in most cases.”

    The area to volume ration of membranes could alter electrical capacitance, and the type of lipid would affect dielectric constant also altering capacitance… pondering.
     
  20. nonchalant

    nonchalant Silver

    That's why Jack is roaming the periodic chart in the Tensegrity series. Quantum forces change the traits of chemicals on the chart (as well as proteins and fats, etc). It's all about size and shape. A crystal prism doesn't give you a beautiful beam of color if it is cloudy and malformed. Like looking at a perfect ice cube verses what I usually find in my icemaker with fluoridated tap water. We need our shape to be perfect in order to benefit from the beautiful color. When I go out into the sun, do I end up with scattered, diffused light inside me, or do I get crystal-clear clarity? Do I get chaos, or do I get instant energy everywhere?
     
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