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Upregulating Lysosomal Activity

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#1 jaydfox

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Posted 17 May 2005 - 04:13 PM

This isn't the same as enhancing the repertoire of lysosomal enzymes proposed by Dr. de Grey, but it is relevant in my opinion.



Chaperone-mediated autophagy (CMA) is a selective lysosomal protein degradative process that is activated in higher organisms under conditions of prolonged starvation and in cell culture by the removal of serum. Ketone bodies are comprised of three compounds (â-hydroxybutyrate, acetoacetate and acetone) that circulate during starvation, especially during prolonged starvation. Here we have investigated the hypothesis that ketone bodies induce CMA. We found that physiological concentrations of â-hydroxybutyrate (BOH) induced proteolysis in cells maintained in media with serum and without serum; however, acetoacetate only induced proteolysis in cells maintained in media with serum. Lysosomes isolated from BOH-treated cells displayed an increased ability to degrade both glyceraldehyde-3- phosphate dehydrogenase and ribonuclease A, substrates for CMA. Isolated lysosomes from cells maintained in media without serum also demonstrated an increased ability to degrade glyceraldehyde-3-phosphate dehydrogenase and ribonuclease A when the reaction was supplemented with BOH. Such treatment did not affect the levels of lysosome-associated membrane protein 2a or lysosomal heat shock cognate protein of 70 kDa, two rate-limiting proteins in CMA. However, pretreatment of glyceraldehyde-3- phosphate and ribonuclease A with BOH increased their rate of degradation by isolated lysosomes. Lysosomes pretreated with BOH showed no increase in proteolysis suggesting that BOH acts on the substrates to increase their rates of proteolysis. Using Oxyblot™ analysis to detect carbonyl formation on proteins, one common marker of protein oxidation, we showed that treatment of substrates with BOH increased their oxidation. Neither glycerol, another compound that increases in circulation during prolonged starvation, nor butanol or butanone, compounds closely related to BOH, had an effect on CMA. The induction of CMA by ketone bodies may provide an important physiological mechanism for the activation of CMA during
prolonged starvation.

#2 John Schloendorn

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Posted 18 May 2005 - 12:03 AM


Why exactly does everyone call this a "ketone body"?!


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Posted 18 May 2005 - 08:39 AM

If you recall your organic chemistry: hydroxybutyrate consists of a 4 carbon molecule with the 1st carbon with a hydroxyl group and a ketone group (carbon double bonded to an oxygen), followed by a hydroxyl group attached to one of the three following carbons, ie HOOC-CHO-CH2-CH3. This structure should remind you of a fatty acid, ie HOOC-CHO-CH2-CH2-R. Ketone bodies include acetone (CH3-CO-CH3), acetoacetate (CH3-CO-CH2-COOH) and ... hydroxybutyrate. The alpha, beta and gamma pertains to which carbon (excluding the one with the ketone group) the hydroxyl group is attached to.

#4 John Schloendorn

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Posted 18 May 2005 - 10:47 AM

The COOH function is an acid. Calling this a ketone would cause any organic chemistry teacher cry in despair, first because of the very different chemistry of these groups and then because it's really outside of any convention.

(If you want to ignore this for some reason, you'd still be wrong, because a ketone is a CO flanked by other Cs. At the end of the molecule it would be called an Aldehyde.)

Aside, although you describe it correctly, your structure is missing a H. It would be HOOC-CHOH-CH2-CH3. (Yours actually is a ketone.) Fatty acids don't have any alpha group either.


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Posted 18 May 2005 - 12:41 PM

You are right, it is an aldehyde at the end and is only a ketone if the C=O is flanked by carbons. Just to be sure I checked it on Stryer.

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