This story has three parts: Met salvage, catabolism, and urology. And it spans three decades of missing research.
L-Methionine (Met) is an essential amino acid. Its use is to take part in Met-RNA and protein biosynthesis, and the synthesis of S-Adenosylmethionine (SAM). In all cases it is recycled. Even when SAM is used to produce polyamines, the sulfur is recycled to Met via the Met salvage pathway. However, if you take a Met overdose -- say 1 or 2 grams orally -- the excess doesn't show in the blood for long, and is degraded or changed quickly. It appears to be well known[1] that this excess leads to an excess of sulfate which is excreted with urine. Around 1985, at least two reactions were hypothesized for excess Met -- transamination to 4-methylthio-2-oxobutanoate (MOB) and transmethylation-transsulfuration via SAM, homocysteine and cystathionine -- with inconclusive results on which is the main path[2]. The transamination reaction to MOB certainly plays a role[3] but where the sulfate comes from quantitatively (MOB or cystathionine) is still unclear, as well as the whole regulation issue in such a tightly regulated system. Possibly the location, cytosol or mitochondria, makes a difference. Meanwhile, a review elucidated the cysteine catabolic branch[4]. So, a complete characterization of the Met-catabolic pathway via transamination -- or the proof of it being irrelevant awaits the trophy-hungry lab rat.
Additionally, in the Met salvage pathway, we don't know exactly the human gene producing the necessary methylthioribulose 1-phosphate dehydratase activity (EC 4.2.1.109). From homology to yeast, it might be APIP but the human activity was never shown. And finally, while transamination to and from Met is proven, which of the many transaminases has that broad specificity to also take on Met? Our guess it's the GGT but noone bothered to test it for decades.
Finally, the sulfate excretion accounting for the acidification potential of Met[5], according to my urologist, this is the only compound with that effect on humans. There may be also ammonium chloride (ref?). Okay, there is the n=60 study[6] showing diluted vinegar being effective in urinary tract infection (UTI), but would you drink it daily to prevent infections? Surprisingly, although the beneficial effect of low pH urine for UTI prevention is beyond doubt, there is no clinical study using Met for this. It would be so easy, the pH test strips and Met itself are inexpensive, so please someone take up this piece of Unsexy Science!
Refs:
1. Mudd, S. H., and H. L. Levy. 1983. Disorders of Transsulfuration. In: The Metabolic Basis of Inherited Disease. 5th edition. J. B. Stanbury, J. B. Wyngaarden, D. S. Fredrickson, J. L. Goldstein, and M. S. Brown, editors. McGraw-Hill Book Co., Inc., New York. 522-559. (unchecked)
2. J. D. Finkelstein, J. J. Martin: Methionine metabolism in mammals. Adaptation to methionine excess. In: J biol chem 261, 4, 1986, 1582–1587. PMID 3080429.
3. W. A. Gahl, I. Bernardini et al.: Transsulfuration in an adult with hepatic methionine adenosyltransferase deficiency. In: J clin. invest. 81, 2, 1988, 390–397. doi:10.1172/JCI113331. PMID 3339126. PMC 329581.
4. M. H. Stipanuk, I. Ueki: Dealing with methionine/homocysteine sulfur: cysteine metabolism to taurine and inorganic sulfur. In: Journal of inherited metabolic disease 34, 1, 2011, 17–32. doi:10.1007/s10545-009-9006-9. PMID 20162368. PMC 290177. (Review)
5. D. L. Bella, M. H. Stipanuk: Effects of protein, methionine, or chloride on acid-base balance and on cysteine catabolism. In: Am J phys 269, 5 Pt 1, 1995, E910–E917. PMID 7491943.
6. Y. C. Chung, H. H. Chen, M. L. Yeh: Vinegar for Decreasing Catheter-Associated Bacteriuria in Long-Term Catheterized Patients : A Randomized Controlled Trial. In: ''Biological research for nursing'' epub 2011. doi:10.1177/1099800411412767. PMID 21708892.
2011-09-03
The case of the one hand clapping
Fatty acid synthesis happens alike in all organisms. Like an assembly line parts are hung onto a template until it grows to a long chain. The template is fixed to a bench, the ACP protein domain, and half a dozen enzymes are at work around it, and with recurring activity, to perform the task until the required length results. In one of the steps an acyl moiety is fused to a malonyl moiety and the chain so elongated. Imagine my surprise when I found everywhere the reaction depicted as
acyl-ACP + malonyl-ACP = 3-oxoacyl-ACP + CO2 + ACP [3]
Twice ACP? That would be fine in mitochondria or bacteria, as there the ACP domain is on a separate protein and, well, let's just take two of them. But in animals' cytosol all enzymatic and ACP domains are on a single enzyme, the fatty acid synthase (FAS). Now, this FAS is a dimer in nature, which could account for the second ACP. Theoretically. We learn from the literature[1] that both monomers are sandwiched in a way that both ACP domains are far apart. Moreover, it is known[2] that the dimer can only contain one phosphopantethein (PPT) per dimer, and this also means, only one usable ACP domain.
Well, I would say one of the ACPs in the reaction actually is CoA in cytosol of animals but who is inclined to show it experimentally? Certainly not the pharma industry. The subject of mostly known physiology is boring, nothing wholly surprising or monetary is to expect. It's all Unsexy Science!
Ref.:
1. A. Witkowski, V. S. Rangan et al.: Structural organization of the multifunctional animal fatty-acid synthase. In: European journal of biochemistry / FEBS 198, Nr 3, June 1991, 571–579. PMID 2050137
2. A. Jayakumar, M. H. Tai et al.: Human fatty acid synthase: properties and molecular cloning.'' In: ''Proceedings of the National Academy of Sciences of the United States of America'' V 92, Nr 19, September 1995, 8695–8699. PMID 7567999. PMC 41033
3. IUBMB Enzyme Nomenclature, EC 2.3.1.41 Website
acyl-ACP + malonyl-ACP = 3-oxoacyl-ACP + CO2 + ACP [3]
Twice ACP? That would be fine in mitochondria or bacteria, as there the ACP domain is on a separate protein and, well, let's just take two of them. But in animals' cytosol all enzymatic and ACP domains are on a single enzyme, the fatty acid synthase (FAS). Now, this FAS is a dimer in nature, which could account for the second ACP. Theoretically. We learn from the literature[1] that both monomers are sandwiched in a way that both ACP domains are far apart. Moreover, it is known[2] that the dimer can only contain one phosphopantethein (PPT) per dimer, and this also means, only one usable ACP domain.
Well, I would say one of the ACPs in the reaction actually is CoA in cytosol of animals but who is inclined to show it experimentally? Certainly not the pharma industry. The subject of mostly known physiology is boring, nothing wholly surprising or monetary is to expect. It's all Unsexy Science!
Ref.:
1. A. Witkowski, V. S. Rangan et al.: Structural organization of the multifunctional animal fatty-acid synthase. In: European journal of biochemistry / FEBS 198, Nr 3, June 1991, 571–579. PMID 2050137
2. A. Jayakumar, M. H. Tai et al.: Human fatty acid synthase: properties and molecular cloning.'' In: ''Proceedings of the National Academy of Sciences of the United States of America'' V 92, Nr 19, September 1995, 8695–8699. PMID 7567999. PMC 41033
3. IUBMB Enzyme Nomenclature, EC 2.3.1.41 Website
About this blog
Half the cup was full when my urologist told me the only medicine that can acidify urine was no longer paid by german health insurance, due to missing evidence of its activity, despite all urologists knowing about it. However, I do not complain about this decision, as it is in line with refusal to pay for quack homeopathics and other nonsense. The second half of the cup filled when I researched physiology data about fatty acid synthesis and found an apparently unrecognized problem. As this is not the first (or even the dozenth) time I find a hole in our physiological knowledge about humans, it finally got me started for a collection of such knowledge holes, as there is no database I could contribute these to.
Now you know what to expect. I am a private biocurator who normally reads papers about the tuberculosis bacterium to create a database that contains physiology knowledge about this organism. Such databases are used by laboratory researchers to make sense of experimental data from microarrays and other high-throughput experiments. So you can say I have an overview. And I see that, frequently, not all experiments are done that would be necessary to elucidate a pathway or process because, admit it, it's just sexier to find something unexpected. This means, however, that researchers rely on others to do the work. This expectation is rarely fulfilled. Which leaves us with knowledge holes. Which ones? Read this blog.
Now you know what to expect. I am a private biocurator who normally reads papers about the tuberculosis bacterium to create a database that contains physiology knowledge about this organism. Such databases are used by laboratory researchers to make sense of experimental data from microarrays and other high-throughput experiments. So you can say I have an overview. And I see that, frequently, not all experiments are done that would be necessary to elucidate a pathway or process because, admit it, it's just sexier to find something unexpected. This means, however, that researchers rely on others to do the work. This expectation is rarely fulfilled. Which leaves us with knowledge holes. Which ones? Read this blog.
Subscribe to:
Posts (Atom)