April 19, 2007 | David F. Coppedge

Fatty Acid Synthesis: A Machine with “High Degree of Architectural Complexity”

As Bruce Alberts said in 1998, the biology of the future was going to be the study of molecular machines: “the entire cell can be viewed as a factory that contains an elaborate network of interlocking assembly lines, each of which is composed of a set of large protein machines.”1  One of those machines is like a mini-factory in itself.  It’s called fatty acid synthase (FAS).  Three Yale researchers just published the most detailed description of this machine in the journal Cell.2  (cf. last year’s headline, 03/06/2006).  They remarked that its most striking feature is the “high degree of architectural complexity” – some 48 active sites, complete with moving parts, in a particle 27 billionths of a meter high and 23 billionths of a meter wide.
    Despite our aversion to fat, fatty acids are essential to life.  It’s when fat production goes awry that you can become fat.  The authors explain:

Fatty acids are key components of the cell, and their synthesis is essential for all organisms except archaea.  They are major constituents of cellular membranes and are used for posttranslational protein modifications that are functionally important.  Saturated fatty acids are the main stores of chemical energy in organisms.  Deregulation of fatty acid synthesis affects many cellular functions and may result in aberrant mitosis, cancer, and obesity.

The chemical steps for building fatty acids appear in the simplest cells and remain essentially unchanged up to the most complex organisms, although the machinery differs widely between plants, animals and bacteria.  In plants, for instance, the steps are performed by separate enzymes.  In animals, a two-part machine does the work.  Which organism has one of the most elaborate fatty-acid machines of all?  The surprising answer: fungi.  The researchers imaged the fatty acid synthase enzymes of yeast and, despite their academic restraint, were clearly excited as the details came into focus:

Perhaps the most striking feature of fungal FAS is its high degree of architectural complexity, in which 48 functional centers exist in a single … particle.  Detailed structural information is essential for delineating how this complex particle coordinates the reactions involved in many steps of synthesis of fatty acids…. The six alpha subunits form a central wheel in the assembly, and the beta subunits form domes on the top and bottom of the wheel, creating six reaction chambers within which each ACP can reach the six active sites through surprisingly modest movements.  This structure now provides a complete framework for understanding the structural basis of this macromolecular machine’s important function.

Calling it an “elegant mechanism,” they proudly unveiled a new model that tells the secret inside: a swinging arm delivers parts to eight different reaction centers in a precise sequence.
    Their dazzling color diagrams are, unfortunately, copyrighted inside a technical journal, but a Google image search shows one reasonable facsimile of the overall shape at a Swiss website: click here.  Some of the protein parts provide structural support for the delicate moving parts inside.  Taking the structure apart, it looks something like a wagon wheel with tetrahedron-shaped hubcaps above and below.  Picture a horizontal wagon wheel with three spokes, bisecting the equator of the structure.  Now put the hubcaps over the top and bottom axles.  The interior gets divided up into six compartments (“reaction chambers”) where the magic takes place.
    In each reaction chamber, eight active sites are positioned on the walls at widely separated angles from the center.  Spaced nearly equidistant between them all is a pivot point, and attached to it by a hinge is a lever arm.  This lever arm, called ACP, is just the right length to reach all of the reaction sites.  From a tunnel on the exterior, the first component arrives and is fastened to the ACP arm (priming).  The arm then swings over to another active site to pick up the next part, then cycles through the next six reaction sites that each do their part to add ingredients to the growing fatty acid chain (elongation).  The machine cycles through the elongation step multiple times, adding carbons to the growing fatty acid.  When the chain reaches its proper length (16-18 carbons, depending on the fatty acid needed), it is sent to a final active site that stops the cycle (termination) and delivers the product through an exit channel to the cytoplasm.
    The ACP hinged arm, then, is the key to the system.  Imagine a life-size automated factory with a roughly spherical interior.  Its task is to build a chain of parts in a precise order.  The first ingredient comes through a shaft and is attached to the robotic arm in the center.  The arm then follows a pre-programmed sequence that holds out the product to eight different machines on the walls that add their part to the product.  The final operation of the arm delivers the product to an exit channel.  In a cell, though, how does this arm actually move?  The answer: electricity.
    Yes, folks, yeast cells contain actual electrical machines.  Don’t visualize wires of flowing current; instead, picture active sites with concentrations of positive and negative charges in precise amounts.  How does the lever arm use this electrical system?  Owing to the specific kinds of amino acids used, each active site has a net positive charge, while the ACP lever arm has a negative charge.  Each time a part is added to the product, it changes the overall charge distribution and makes the arm swing over to the next position.  Thus, a blind structure made out of amino acids follows a cyclic pattern that builds up a specific product molecule one carbon at a time, and automatically delivers it when complete.  After delivery, the system is automatically reset for the next round.  Clearly, the precision of charge on each active site is critical to the function of the machine.3, 4
    Now that we have described one reaction chamber, step back and see that the yeast FAS machine has six such chambers working independently and simultaneously.  Another surprise is that the lever arm inside must be activated from the outside during assembly of the machine by a structure (PPT) on the exterior wall before it can work.  There’s a reason for this, too:

The crystal structure of yeast FAS reveals that this large, macromolecular assembly functions as a six-chambered reactor for fatty acid synthesis.  Each of the six chambers functions independently and has in its chamber wall all of the catalytic units required for fatty acid priming, elongation, and termination, while one substrate-shuttling component, ACP, is located inside each chamber and functions like a swinging arm.  Surprisingly, however, the step at which the reactor is activated must occur before the complete assembly of the particle since the PPT domain that attaches the pantetheine arm to ACP lies outside the assembly, inaccessible to ACP that lies inside.  Remarkably, the architectural complexity of the FAS particle results in the simplicity of the reaction mechanisms for fatty acid synthesis in fungi.

Maybe the activation step is a quality-control step, to ensure the system doesn’t cause trouble in the cytoplasm before the machinery is completely assembled.
    The authors did not mention how fast the synthesis takes place.  But if it’s anything like the other machinery in the cell, you can bet the FAS machine cranks out its products swiftly and efficiently, and life goes on, one molecule at a time.  Baking a cake with yeast will never seem the same again.


1See 01/09/2002 for citation.
2Lomakin, Xiong and Steitz, “The Crystal Structure of Yeast Fatty Acid Synthase, a Cellular Machine with Eight Active Sites Working Together,” Cell, Volume 129, Issue 2, 20 April 2007, Pages 319-332.
3In addition to electrical charges, some amino acids have side chains that attract or repel water.  These hydrophilic and hydrophobic side chains also contribute to the force fields that cause the conformational changes in the enzyme.
4The diagrams in the paper show the details of each active site.  To the uninitiated, enzyme models appear like random balls of putty stuck together, but humans should not impose their propensity for straight lines and angles on the world of molecules.  The shape and folds of the structure are critical to the function because they control the charge distribution in the vicinity.  The active sites are recessed within tunnels.  The ACP lever arm tip is guided by charge into these tunnels where ingredients are “snapped on” to the molecule through precise chemical reactions.  Each reaction changes the charge distribution, leading to the next stage of the cycle.

Reading this paper was almost a transcendent experience.  To imagine this level of precision and master-controlled processing on a level this small, cannot help but induce a profound sense of wonder and awe.  Here, all this time, this machine has been helping to keep living things functioning and we didn’t even know the details till now.  How would such revelations have affected the history of ideas?
    The authors did not say a peep about evolution except to note five times that certain parts are “conserved” (unevolved).  They also assumed evolution (without evidence) in one astonishing reaction to the fact that certain folds in the protein parts of this machine are unique in nature: listen – “They consequentially represent new folds and may have evolved independently to tether and orient the multiple active centers of fungal FAS for efficient catalysis.”  OK, everyone, a collective rotten-tomato toss for that enlightened suggestion.
    Remember that origin-of-life researchers are stumbling and fumbling trying to get even single amino acids to form (04/04/2007), let alone get them to join up in useful, functioning chains (see online book).    The fatty acids are useless without the amino acids, and vice versa (09/03/2004).  Even if some kind of metabolic cycle were to be envisioned under semi-realistic conditions, how did this elaborate machine, composed of amino acids with precise charge distributions, arise?  It’s not just the machine, it’s the blueprints and construction process that must be explained.  What blind process led to the precise placement of active sites that process their inputs in a programmed sequence?  What put them into a structure with shared walls where six reaction chambers can work independently?  All this complexity, involving thousands of precision amino acids in FAS (2.6 million atomic mass units) has to be coded in DNA, then built by the formidably complex translation process, then assembled together in the right order, or FAS won’t work.  But the storage, retrieval, translation and construction systems all need the fatty acids, too, or they won’t work.
    We are witnessing an interdependent system of mind-boggling complexity that defies any explanation besides intelligent design.  Yes, Bruce Alberts, “as it turns out, we can walk and we can talk because the chemistry that makes life possible is much more elaborate and sophisticated than anything we students had ever considered.”  We have tended to “vastly underestimate the sophistication of many of these remarkable devices.
    Yeast.  Who could have ever imagined this simple little blob possessed a high degree of architectural complexity and robotic technology.  Many questions remain.  Why do plants and animals have different mechanisms, but the same chemical steps?  Why do fungi, of all things, have the most elaborate architectures?  Are the other architectures equally complex in their own ways?  What other factories regulate this one, and how does this factory regulate other downstream systems?  We have much more to learn about fatty acid synthesis, but the “biology of the future” – design biology – is shedding far more light than Darwin’s myths ever did.  The fact that life functions so well, from yeast to human, should spur us on to uncover the design principles that make it all come together as a finely tuned system, in a finely tuned world, in a finely tuned universe.

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