section 21.6
Drugs Affecting Microtubules
483
D y n e in
arm s
B a s e of cilium
(a)
FIGURE 21-18
Sliding of one microtubule along another in an intact cilium causes the
cilium to bend, creating a power stroke.
and are believed to form a fixed attachment of the dynein
complex to the A microtubule, and they probably play a
role in regulating the activity of the dynein, although not
much is known about the regulatory mechanisms. As with
myosin, there are multiple dynein genes, and the axoneme
contains eight or more different heavy chains. The outer
dynein arms have two or three heavy chains; the inner arms
have two.
The scheme of chemomechanical transduction by
dynein-tubule systems is similar in a general way to that in
myosin-actin systems, but the structure of dynein is very
different from that of myosin. Force generation begins by
formation of a dynein cross-bridge to the adjacent B mi-
crotubule. This is followed by a conformational change in
the dynein that pulls the two microtubules past each other.
Dynein is a (—)-directed motor, i.e., it tries to pull its base
toward the end of the adjacent microtubule, which is to-
ward the basal body in cilia and flagella. Free energy of
hydrolysis of ATP is required to release the dynein head
and allow the dynein bridge to recycle. As in the case
of actomyosin ATPase, it is thought that the coupling of
ATP hydrolysis to mechanical movement is effected at the
product release step and that this step is rate limiting.
Since the microtubules are all fixed at one end, the
only way they can slide past one another is to bend
(Figure 21-18). Activation of the dynein seems normally
to occur from the base to the outer tip.
21.6 Drugs Affecting Microtubules
Microtubule systems are used in the cell for many other
functions, such as transport of organelles and vesicles,
and separating genetic material on the mitotic spindle and
other motile events of the cell cycle. Substances that inter-
fere with microtubule growth or turnover, or with micro-
tubule interaction with motor proteins, will disrupt these
functions. The classic example of such a drug is
colchicine,
an alkaloid derived from the autumn crocus
(Colchicum
autumnale).
Colchicine in high concentration causes cy-
tosolic microtubules to depolymerize. In low concentra-
tions, it does not produce this effect, but binds to tubulin
dimers. The tubulin-colchicine complex, even at quite low
concentration, can add on to the end of a growing (or at
least stable) microtubule and block further reactions at that
end. Only one or two colchicine-tubulin units at the end of
a microtubule prevents any further addition or removal of
dimers at that end. In cells that are replicating, this freezes
the cell at metaphase. Drugs that produce such an effect are
useful as
antineoplastic agents.
The well-known effect of
colchicine in gouty arthritis is probably due to its inhibit-
ing the migration of granulocytes into the inflammatory
area by interfering with a microtubule-based component
of their motility.
Vinca alkaloids (vincristine, vinblastine, vinorelbine)
are derived from the periwinkle plant
(Vinca rosea).
These
agents work by binding to tubulin at a site different
than colchicine or paclitaxel. They block polymerization,
which prevents the formation of the mitotic spindle, and
are used as antineoplastic agents. Taxanes produce a sta-
bilization of microtubules similar to colchicine, but by
a different mechanism, and also halt cells in metaphase.
Paclitaxel (taxol) is the taxane used clinically. It is de-
rived from the bark of the pacific yew. Taxol disrupts
several microtubule-based functions as completely as in-
hibitors of polymerization, emphasizing the importance
of assembly/disassembly balance in microtubule function.
Recently, it has been found that paclitaxel also binds to and
inhibits the function of a protein called bcl-
2
, an inhibitor
of one or more pathways involved in mediating apopto-
sis. Paclitaxel’s interference with this function promotes
apoptosis in addition to its microtubule-related inhibition
of cell division.
Immotile Cilia Syndrome
Defects in proteins needed for normal assembly and func-
tioning of microtubules can cause cellular dysfunction.
Several inherited disorders of this type have been identi-
fied that cause dyskinetic or completely immotile cilia and
flagella. Kindreds have been identified in whom dynein
arms, radial spokes, central sheath, or one or both cen-
tral singlets are missing or defective. These disorders may
result from a mutation in a gene needed for one of the
axonemic structures, or in a regulatory gene controlling
assembly of the microtubule system in cilia and flagella.
Affected
individuals
manifest
bronchiectasis
and
chronic sinusitis. Because the cilia of the respiratory ep-
ithelium are defective, mucociliary clearance is reduced
