Protein Carbamylation is Associated with Aging
Chemical reactions leading to modification of long-lived proteins in tissues, such as those making up the extracellular matrix or that occupy important positions in nerve cells, are a source of damage and dysfunction. Proteins can only perform correctly when they possess the right structure: modify that structure and problems arise. Degenerative aging is, at root, nothing more than an accumulation of damage, but there remains a lot of room to debate which specific types of damage might be more or less important than others over the present span of human life. One of the better known classes of damaging modification to proteins is produced by reactions with sugar compounds, particularly advanced glycation end-products (AGEs) such as glucosepane, but this is far from the only type of modification that occurs in the complex biology of a living individual. In the research noted here, for example, the authors add data to what is know about carbamylation of proteins.
Definitively establishing the relative degrees of significance of different forms of protein modification will probably require a means of clearing out and reversing each of these chemical reactions: given that technology, run the test and see what happens. This is somewhat complicated by the fact that species with different life spans tend to have radically different relationships with the various types of damaging protein modification. This has been amply demonstrated over the past twenty years of work on AGEs: those relevant to long-term health in mice and rats are not particular relevant in humans, and vice versa, a unfortunate circumstance that led to failure for the first efforts to produce treatments capable of clearing AGEs.
Chemical reactions referred to as nonenzymatic posttranslational modifications (NEPTMs), such as glycoxidation, are responsible for protein molecular aging. Carbamylation is a more recently described NEPTM that is caused by the nonenzymatic binding of isocyanate derived from urea dissociation or myeloperoxidase-mediated catabolism of thiocyanate to free amino groups of proteins. This modification is considered an adverse reaction, because it induces alterations of protein and cell properties. It has been shown that carbamylated proteins increase in plasma and tissues during chronic kidney disease and are associated with deleterious clinical outcomes, but nothing is known to date about tissue protein carbamylation during aging.To address this issue, we evaluated homocitrulline rate, the most characteristic carbamylation-derived product (CDP), over time in skin of mammalian species with different life expectancies. Our results show that carbamylation occurs throughout the whole lifespan and leads to tissue accumulation of carbamylated proteins. Because of their remarkably long half-life, matrix proteins, like type I collagen and elastin, are preferential targets. Interestingly, the accumulation rate of CDPs is inversely correlated with longevity, suggesting the occurrence of still unidentified protective mechanisms. In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations. Thus, protein carbamylation may be considered a hallmark of aging in mammalian species that may significantly contribute in the structural and functional tissue damages encountered during aging.
Hey,
''Interestingly, the accumulation rate of CDPs is inversely correlated with longevity... In addition, homocitrulline accumulates more intensely than carboxymethyl-lysine, one of the major advanced glycation end products, suggesting the prominent role of carbamylation over glycoxidation reactions in age-related tissue alterations''
This is intriguing. Protein carbamylation/carbamoylation is another contributor to the intrinsic aging problem.
CML carboxymethyl-lysine is another AGEs contributor. Sometimes, I am guessing that really aging is really an accumulation of all these damages, and all of them need to be removed; for studies that show inverse correlation between one damage and lifespan; show causation and correlation; but only part of it. Other damages chime in this and contribute too. That is why we couldn't logically think AGEs removal alone such as CML, furosine, pentosidine, glucosepane could Entirely reverse aging; but you would need removal of protein adduct damages like 4-HNE (4-hydroxynonenal) and Acrolein (rarer but extremely reactive and damaging);
L- to D- racemic aging amino conversion (L-aspartate to D-aspartate); protein carbamylated products (homocitrulline); 8-/f2 Isoprostanes and prostaglandins E2, DNA lesions (8-oxodG), DSBs/SSBs and deletions (mitochondrial 4977-bp common deletion and recently identified UVB-induced deletion of 5128-bp in normal skin), Telomere replicative-end bp loss and pigments/plaques accumulation (lipofuscin, ceroid, amyloids, transthyretin, ...); and on and on....
It is as if as we continue to study aging, newer damages appear and are never ending. How could we think we could repair them All ? I am guessing we will have to repair Most of them to get Good enough rejuvenation and it will be Good enough to give us a strong lifespan extension; immortality unlikely though, untile we pin them all down and remove them all. Perhaps, that is where damage repair fails (there are just too many of them) and reprogrammation wins (how exactly it removes *All these irreversible accumualted damages I'm not sure, but most likley genes programming could possibly do that).
This study is interesing because it talks about homocitrulline, a carbamylation product; which ties in directly to another carbamylation-creating product : homocysteine. Both are related amino acids who got homo prefix, the difference is one is in entire control of the Redox.
Homocysteine is the bane and the crux of the Redox. (which is also under SAM:SAH control, S-Adenosyl-Methionine and S-Adenosyl-Homocysteine ratio in transsulfuration pathway). I am not surprised one bit the Redox homeostatic loss behind all of these chain events, including protein carbamoylation.
''Protein N-Homocysteinylation Induces the Formation of
Toxic Amyloid-Like Protofibrils''
''In addition, carbamoylation of α-crystallins
contributes to the development of cataract9 and
extensive protein glycation is thought to contribute
to the Alzheimer's disease pathogenesis.10 In
contrast, the reaction of cyanate with proteins can
induce protein stabilization, favoring their physiological
function.
Homocysteine thiolactone (HTL), a metabolite
produced by methionyl-tRNA synthetase in an
error-editing reaction in protein biosynthesis,12
reacts with proteins, causing loss of function and
aggregation.13,14 In cells, the rate of HTL synthesis is
strictly dependent on the levels of the precursor
metabolite, homocysteine.15,16 In healthy humans,
some enzymes catalyze the reconversion of homocysteine
into either methionine or cysteine, contributing
to maintain very low concentrations of this
metabolite. Nevertheless, some conditions such as a
diet particularly rich in methionine; mutations or
inactivation of cystathionine β-synthase, methionine
synthase, and 5,10-methylene tetrahydrofolate reductase;
and nutritional deficiencies of vitamins
(folic acid or vitamin B12) induce a dramatic
increase of cellular homocysteine concentration,
with the resulting increase in the rate of HTL
synthesis17 and increased accumulation of N-Hcyprotein
in humans and mice.18,19 Although different
hypotheses have been proposed to describe the
pathological consequences of hyperhomocysteinemia
in humans.
It has been
reported that the N-homocysteinylation of four
lysine residues of cytochrome c causes structural
changes in the protein affecting the redox state of the
heme group.25,26 In addition, N-homocysteinylation
causes protein aggregation,13–21 which has been
documented for several proteins, including human
serum albumin (HSA).''
Happy New Year!
Protein N-Homocysteinylation Induces the Formation of
Toxic Amyloid-Like Protofibrils
1. http://biochemistry.sbmu.ac.ir/uploads/protein_homocysteinylation.pdf
Reassuringly, from the full text:
Carbamylated Proteins Are Partly Eliminated from the Organism. To
study the potential turnover of carbamylated proteins in vivo, we
used a mouse model of dietary cyanate-induced carbamylation corresponding
to a feeding with cyanate-supplemented water [drinking
water containing 15 mM sodium cyanate (Cy-drink)]. After 3 wk,
HCit significantly increased in plasma and skin in the Cy-drink group
compared with the group given nonsupplemented water (Wa-drink),
with values being higher than 38 mmol HCit/mol Lys vs. less than
1 mmol HCit/mol Lys, respectively. When cyanate consumption was
continued until 12 wk, HCit contents further accumulated in skin,
whereas they did not vary anymore in plasma (Fig. 6A). By contrast,
when Cy-drink over 3 wk was replaced by Wa-drink, HCit
progressively decreased over time. The decrease was almost
complete in plasma (−99%), whereas it was only partial in total
skin extract (−70%) and especially, collagen (−45%) after 9 wk (P < 0.01) (Fig. 6B). The authors are trying to make the case that this is too slow for comfort, but I'd say it is amply fast enough for comfort. However, I'll be trying to find out more: is this carbamylation reaction spontaneously reversible, like the first steps in glycation? Is it (like glycation) sometimes followed by other reactions, especially ones that can lead to crosslinks? That sort of thing.
So higher serum levels of urea contribute to carbamylation. Does drinking more water, which lowers urea concentrations, therefore lower carbamylation? The article linked below also seems to suggest that Ammonium Bicarbonate will reduce carbamylation as well. Thoughts on drinking more water and supplementing with bicarbonate to reduce aging skin via reduced carbamylation?
http://www.biosyn.com/tew/Carbamylation-in-aging-and-disease.aspx
recent info. https://www.ncbi.nlm.nih.gov/pubmed/26712018 " Carbamylation is a hallmark of aging"