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It's almost half a century since the lac operon was discovered but isn't it weird that the precise role of transacetylase isn't clearly understood ?

Here a wikipedia article with a link to a journal article which proposes a function of this enzyme. This article was written in 2002 but in most of the text books I have referred to ( written well after 2002 ), no function is mentioned.

MY QUESTION : What are the difficulties that are not allowing us to understand the precise role of this enzyme ?

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the mechanism of the reaction catalysed by this enzyme is understood. what is not understood is why is this reaction important. perhaps it increases the rate of lactose metabolism in some conditions. knockouts cannot always elucidate roles of genes because there may be only a set of conditions when they play an important role. –  WYSIWYG Nov 4 '13 at 16:16
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+50

Note: This is NOT my field. However, given @biogirl's question, it appears that there aren't many people in this field in the first place. From what I can gather, here are the reasons why I think it has been difficult to study.

I. The lac operon has strong polarity. By this I mean that when the lac operon is induced, lacZ (the first gene in the operon) is translated much more than lacA (the last gene in the operon). Measurements have recorded the molar ratio of $\beta$-galactosidase : thiogalactoside transacetylase (the protein products of lacZ and lacA) upon induction of the operon at 3:1 to 5:1; i.e. when the lac operon is induced 3 to 5 molecules of $\beta$-gal are produced for every one of the transacetylase. If you factor in the relative length of each of these proteins ($\beta$-gal is 1024 a.a.s, transacetylase is 203), it works out that lacZ is being translated at least 10 times faster than lacA when the lac operon is induced. Sidney Altman's lab has attributed this to the fact that there is a cleavage site between lacY and lacA where RNAses can cleave the nascent mRNA transcript, removing lacA from the operon and reducing the production rate of transacetylase. So it appears the cell needs quite a bit less lacA than lacZ---if indeed they need it at all, see point 2---which makes it harder to study.

Sources: Brown JL, Brown DM, Zabin I. (1967). J Biol Chem. 242(18):4254-8.

Li Y, Altman S. (2004). J Mol Biol. 339(1):31-9.

II. lacA seems to provide only a small fitness advantage under somewhat contrived conditions. In A paper from the 70s researchers presented competition experiments between $lacA^{+}$ and $lacA^{-}$ strains in media with $\beta$-galactosides as the only carbon source. For 50 generations there was no competitive advantage of one strain over the other (ratio of $lacA^{+}$ : $lacA^{-}$ stayed at 1). When after 50 generations the researchers added a lot of IPTG, a non-hydrolyzable $\beta$-galactoside, $lacA^{+}$ outcompeted $lacA^{-}$; the absolute fitness of wild-type:mutant could be calculated to be $\approx 1.05$. This means that the wild-type produced 105 cells for every 100 produced by the mutant. I am not a population geneticist, so I don't know if that is a large value or not. For comparison, I used to work in cyanobacterial circadian rhythms, and the absolute fitness advantage for having a circadian clock with the same period as the light-dark cycle in the environment works out to $>1.11$, which is twice as advantageous as the one reported for $lacA^{+}$ over $lacA^-$. In any case, the experimental situation in which $lacA^+$ has a competitive advantage seems rather contrived: growing with $\beta$-galactosides as the sole carbon source with a significant amount of non-hydrolyzable analoges around gumming up the $\beta$-galactoside metabolic machinery.

Source: Andrews KJ, Lin EC. (1976). J Bacteriol. 128(1):510-3.

My read from these observations is that the physiological role of lacA is challenging for a biologist to untangle due to the small size of its effect on bacterial physiology. Fitness advantages of 5% may certainly be useful on evolutionary timescales, but they suggest that the benefit afforded by the enzyme will be very hard to discriminate from noise or other confounding factors in the system. The fact that lacA production is much lower than lacZ in times of lac operon induction also would make it hard to measure.

A postdoc I used to work with advised me, "don't go looking for 2-fold changes in biology," by which he meant don't spend too much time on questions where the size of the effect you are looking at is minor and very difficult to distinguish from noise, bias, measurement error, or other confounding variables. Obviously there are limitations to this advice; a lot can be learned from the the combination of several seemingly minor effects that have big cumulative consequences for an organism. But as a rule of thumb, it's so hard to get strong results when your effect size is so small that going after small effects is justifiable only if you have a good reason to believe there is some profound, fundamental biology behind them. My view is that the consensus of the scientific community up to this point has been that untangling the role of lacA in the lac operon and more broadly in bacterial physiology would involve too much work for too little payoff.

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Thank you for your awesome answer ! I would like to point out that 1.1 isn't double of 1.05 so I don't understand how that's twice as advantageous. –  biogirl Nov 9 '13 at 17:25
    
Thanks! It's a great question that I'd wondered about, too, so I had fun thinking about it and looking it up. My reasoning for "twice as advantageous" is that the 1 in 1.1 or 1.05 you kind of get for free: the fitness number 1.1 or 1.05 means that 110 or 105 bacteria are produced in the more fit condition vs. 100 in in the less fit condition. So the fitness difference is really only responsible for an extra 5 or 10 bacteria. So by that measure, a fitness of 1.1 is responsible for twice as many additional bacteria as a fitness of 1.05. Though that might not be the best way to summarize it. –  A. Kennard Nov 9 '13 at 17:33
    
Alright. You have really done a lot of work to find all those references ! –  biogirl Nov 9 '13 at 17:37
    
Saturday well spent? Maybe I shouldn't answer that... –  A. Kennard Nov 9 '13 at 17:39
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