Introduction: Milk Lipid Synthesis: Chain Length Determination and Secretory Differentiation

Abstract

In 1967 Stuart Smith and R. Watts, working with RayDils at the National Institute for Research in Dairying atReading, found that there was very little difference inthe fatty acid composition of the adipose tissue ofdifferent species, while in contrast milk fat had anaverage fatty acid chain length of 11.7 in rabbits, 14.2 inrats,15.3inmice,and17.2inguineapigs[1]. Smithand Dils had previously shown that fatty acids with achain length from 6 to 14 carbons could be synthesized bymammary tissue from lactating rabbits, making it clearthat de novo fatty acid synthesis in the mammary glanddiffered fundamentally from that in other organs [2].Evidence for an independent tissue specific factor in themammary gland that terminated chain elongation earlywas obtained in several laboratories [3]. By 1969 Smithhad moved to the Children’s Hospital Medical Center ofNorthCarolinatoworkwithSandyAbraham;bothheandRay Dils continued to work on this factor, which becameknown as thioesterase II. It was a difficult job, finallysuccessful in 1978 [4]. In the paper reproduced here, thepathway to purification of this factor as well as thegeneral mechanisms of fatty acid synthesis are described[5].Smith describes the circumstances under which hegave the talk at the 74th Annual Meeting of theAmerican Dairy Science in 1979 that resulted in thispublication: “That meeting, held on the campus of UtahStateUniversityinLogan,includedasymposiumonMilk Synthesis. I recall that Nick Kuhn from theUniversity of Birmingham, England, (my alma mater),also gave a talk on lactose synthesis. I don't remembermany details of the meeting except that I arrived at sunseton a small prop plane from Salt Lake City to find that thetiny airport was completely deserted, not a taxi in sight. Iwas rescued by the pilot of our plane who drove me in hiscar directly to my hotel in town. Now that's service youwill not find anywhere these days!”He goes on: “During the five year period leading upto the talk it was established that the animal fatty acidsynthase was a ‘multifunctional polypeptide’ in whichall of the enzymes of that biosynthetic pathway wereintegrated into a single polypeptide. Little did we knowthat it would take another 30 years before the detailedstructure of the complex would be established [6, 7].Nevertheless, at the time of the meeting in Logan, we hadcome to appreciate that all tissues use the same enzymesystem for de novo fatty acid biosynthesis (the fatty acidsynthase), regardless of the products made. In the case ofthe lactating mammary gland, the ability to makemedium-chain saturated fatty acids was dependent onthe presence of a tissue-specific thioesterase (termed‘thioesterase II’) that, remarkably, was able to interruptthe chain elongation process by accessing and hydrolyz-ing the thioester bond linking these intermediates to theprotein. We now know that the resident thioesterase(termed ‘thioesterase I’), which normally terminates chainelongation at 16 carbon atoms, is secured to its neighbor-ing domain by a relatively long flexible tether, whichpresumably allows it to be displaced by the externalthiosterase II thus allowing access to intermediate chainlength intermediates. Nevertheless, the details of how thisis achieved are still to be worked out.”One of the next big questions is how the activity ofthis enzyme is regulated. There is increasing evidence at