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chapter 11
Heteropolysaccharides II: Proteoglycans and Peptidoglycans
Hydroxylysine glycosides occur at the Y-position and may
play a role in determining fibril diameter. The side chains
of these amino acids project outward from the center of
the triple helix, permitting hydrophobic and ionic inter-
actions between tropocollagen molecules. These interac-
tions determine the manner in which individual tropocol-
lagen molecules aggregate to form microfibrils initially,
then larger fibrils, and eventually fibers.
The microfibril, about 4 nm wide, consists of four to
eight tropocollagen molecules that aggregate in a highly
ordered and specific manner owing to interactions of
amino acid residues at the X- and Y-positions. In this
ordered arrangement, each molecule is displaced longi-
tudinally by about one-fourth of its length from its near-
est neighbors. The longitudinally displaced tropocollagen
molecules are not linked, and there is a gap of about 40 nm
between the end of one triple helix and the beginning of
the next (Figure 11-4). These holes may provide sites for
deposition of hydroxyapatite [Caio(P
0 4
)
6
(OH)2] crystals
in the formation of bone (Chapter 37). Electron micro-
scopic studies of negatively stained collagen fibrils reveal
alternating light and dark regions. The light region, where
the stain does not deposit, represents the overlapping of
FIGURE 11-4
Packing of collagen polypeptides into a fibril. The individual tropocollagen
molecules are quarter-staggered with respect to their nearest neighbors by
a distance of 68 nm (D). A gap of about 40 nm (0.6 D) known as the hole
region comes between the end of one tropocollagen molecule and the
beginning of the next. The overlap zones are about 27 nm (0.4 D) in length
and do not contain any hole zones. [Modified and reproduced, with
permission, from A. Cohen, Ed.:
Rheum atology and Im m unology
(W.B. Saunders, 1979).]
tropocollagen molecules; the dark region corresponds to
a hole where the stain is deposited.
The tensile strength of collagen fibrils is determined
by covalent cross-links involving lysyl and hydroxylysyl
side chains. The packing arrangement of tropocollagen
molecules provides tensile strength and also prevents slid-
ing of molecules over one another. This organization does
not allow for stretching, which does occur in elastin. The
nature and extent of crosslinking depend on the physiolog-
ical function and age of the tissue. With age, the density of
cross-linkages increases, rendering connective tissue rigid
and brittle. The arrangement of fiber bundles varies with
the tissue; it is random in bone and skin, sheet-like in blood
vessels, crossed in the cornea, and parallel in tendons.
Turnover of Collagen and Tissue Repair
The catabolism of collagen in the connective tissue ma-
trix is carried out by enzymes known as
collagenases.
Part
of the degradation may also involve neutral proteinases. A
metalloenzyme specific for collagen catalyzes the cleav-
age of the triple helix at a single peptide bond, located
at a distance from its N terminus corresponding to about
three fourths the length of the tropocollagen molecule. The
cleavage sites in type I collagen are the peptide bonds of
Gly-Ile of the a 1-chain and of Gly-Leu of the a 2-chain.
The role and regulation of collagenase activity in vivo are
unclear. The activity of the enzyme may be regulated via
the formation of an enzyme-inhibitor complex or by the
activation of a proenzyme, or both.
A substantial amount (2CM-0%) of newly synthesized
polypeptide chains of collagen undergo
intracellular
degradation.
This degradation, which appears to occur
in lysosomes, may be important in regulating the amount
of collagen synthesized and in removing any defective
or abnormal polypeptide chains that may be synthesized.
Turnover of collagen in humans has been estimated by
measurement of urinary hydroxyproline, which occurs
mostly in the form of a peptide. Hydroxyproline makes
up about 9-13% of collagen residues and is not reutilized.
Two aspects of hydroxyproline metabolism affect its use
in the assessment of the true rate of collagen turnover:
1. Hydroxyproline is rapidly metabolized in a pathway
initiated by the enzyme hydroxyproline oxidase
(Chapter 17).
2. Hydroxyproline is present in Clq, which is
synthesized at a rate estimated to be about 4.5 mg/kg
per day.
The first aspect has been overcome by measurement of
urinary hydroxyproline in individuals with an inherited de-
ficiency of hydroxyproline oxidase. Such persons excrete
