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Structure and synthesis of collagen in the human body

Collagen is the most abundant protein found in mammals, making up about 25 percent of the total proteins in the human body. There are at least 16 types of collagen, but 80 – 90 percent of the collagen in the body consists of types I, II, III and IV. Type I: Makes up the fibers found in connective tissues of the skin, bone, teeth, tendons and ligaments.
Type II: Round fibers found in cartilage.
Type III: Forms connective tissues that give shape and strength to organs, such as the liver, heart, kidneys, etc.
Type IV: Forms sheets that lie between layers of cells in the blood vessels, muscles, and eye.

These collagen molecules pack together to form long thin fibrils of similar structure.  At one time it was thought that all collagens were secreted by fibroblasts in connective tissue, but we now know that numerous epithelial cells make certain types of collagens. The various collagens and the structures they form all serve the same purpose, to help tissues withstand stretching.

The triple-helical structure of collagen arises from an unusual abundance of three amino acids: glycine, proline, and hydroxyproline. These amino acids make up the characteristic, repeating motif Gly-Pro-X, where X can be any amino acid. Each amino acid has a precise function.  Collagen biosynthesis and assembly follows the normal pathway for a secreted protein. The collagen chains are synthesized as longer precursors called procollagens; the growing peptide chains are co-translationally transported into the lumen of the rough endoplasmic reticulum (ER). In the ER, the procollagen chain undergoes a series of processing reactions.

Post-translational modification of procollagen is crucial for the formation of mature collagen molecules and their assembly into fibrils. Defects in this process have serious consequences, as ancient mariners frequently experienced. For example, the activity of hydroxylases requires an essential cofactor, ascorbic acid (vitamin C). In cells deprived of ascorbate, as in the disease scurvy, the procollagen chains are not hydroxylated sufficiently to form stable triple helices at normal body temperature, nor can they form normal fibrils. Consequently, nonhydroxylated procollagen chains are degraded within the cell. Without the structural support of collagen, blood vessels, tendons, and skin become fragile. A supply of fresh fruit provides sufficient vitamin C to process procollagen properly.

The biosynthetic pathway responsible for collagen production is a very complex one. In addition to Vitamin C, collagen crosslinking requires Copper, Iron and Manganese.

Prolyl hydroxylase and lysyl hydroxylase require vitamin C and iron as cofactors. Lysyl oxidase deaminates lysine and hydroxylysine in the first step for collagen crosslinking, and this requires copper (hence the hair and skin signs in Menkes disease).

Linus Pauling

In 1989, the eminent American scientist and two-time Nobel Prize winner, Linus Pauling, announced a breakthrough “A Unified Theory of Human Cardiovascular Disease,” Linus Pauling thought that the deposits of plaque seen in atherosclerosis were not the cause of heart disease, but were actually the result of our bodies trying to repair the damage caused by long-term vitamin C deficiency. In essence, Pauling believed that heart disease is a form of scurvy, and plaque is the body’s attempt to reinforce and patch weakened blood vessels and arteries that would otherwise rupture. Pauling also showed that heart disease can be prevented or treated by taking vitamin C and other supplements.

Plaque Deposits

Pauling based his revolutionary theory on a number of important scientific findings. First was the discovery that plaque deposits found in human aortas are made up of a special form of cholesterol called lipoprotein (a) or Lp(a), not from ordinary LDL cholesterol. Lp(a) is a special form of LDL cholesterol that forms the thick sheets of plaque that obstruct arteries.

Another finding central to Pauling’s theory was the observation that plaque deposits are not formed randomly throughout the circulatory system. This was first reported in the early 1950s when a Canadian doctor, G. C. Willis, MD, observed that plaque always forms nearest the heart, where blood vessels and arteries are constantly being stretched and bent, rather than being spread evenly throughout the entire cardiovascular system. Willis also noted that plaque deposits always occur in regions that are exposed to the highest blood pressures, such as the aorta, where blood is forcefully ejected from the heart.

In 1985, a team of researchers verified that plaque only forms in areas of the artery that become damaged. These small areas of damage expose strands of the amino acid lysine (one of the primary components of collagen) to the blood stream. These strands attract Lp(a). Lp(a) is an especially “sticky” form of cholesterol that is attracted to lysine. Drawn to the break, Lp(a) begins to collect and attach to the exposed strands. As Lp(a) covers the lysine strands, free lysine in the blood is drawn to the growing deposit. Over time, this process continues as lysine and Lp(a) are both drawn from the blood to build ever-larger deposits of plaque. This process gradually reduces the inner diameter of the vessels and restricts its capacity to carry the blood.

Heart Disease as Low-Level Scurvy?

Observing the newly described process of plaque formation, Pauling recognized a similarity to underlying processes seen in scurvy. He also saw similarities between human and animal models of atherosclerosis that pointed to a connection with scurvy. First, cardiovascular disease does not occur in any of the animals that are able to manufacture their own vitamin C. Many animals produce large amounts of vitamin C that are equivalent to human doses ranging from ten to twenty grams per day. Second, the only animals that produce Lp(a) are those which, like man, have also lost the ability to produce their own vitamin C, such as apes and guinea pigs.

Pauling suggested that the ability to form plaque is really the body’s attempt to repair damage caused by a long-term deficiency of vitamin C. Pauling thought that scurvy was one of the greatest threats to humankind’s early survival, and believed that the loss of blood during times of vitamin C deficiency, particularly during the Ice Ages, likely brought humans close to the point of extinction.

Plaque as a Life Saver?

The core of Pauling’s theory is that, over time, the body developed a repair mechanism that allowed it to cope with the damage caused by chronic vitamin C deficiency. When arteries became weak and began to rupture, the body responded by “gluing” the damaged areas together with Lp(a) to prevent a slow death from internal bleeding. In essence, plaque is the body’s attempt to patch blood vessels damaged by low-level scurvy. Accordingly, Pauling believed that conventional “triggers” of plaque formation, such as homocysteine and oxidized cholesterol, are actually just additional symptoms of scurvy.

Collagen Melts Plaque, Keeps Arteries Open

In addition to taking vitamin C to prevent atherosclerosis, Pauling recommended a combination of vitamin C and the amino acids lysine and proline to help remove existing plaque while strengthening weak and damaged arteries. As mentioned previously, the body produces collagen from lysine and proline. Pauling reasoned that by increasing concentrations of lysine and proline in the blood, Lp(a) molecules would bind with the free lysine, rather than with the lysine strands exposed by the cracks in blood vessels.

Pauling Therapy for the Reversal of Heart Disease

  1. Vitamin C: to bowel tolerance – as much as you can take without diarrhea. For most people this will be in the range of five to ten grams (5,000-10,000 mg.) each day. Spread this amount into two equal doses 12 hours apart. (Vitamin C prevents further cracking of the blood vessel wall – the beginning of the disease.)
  2. L-Proline: 3 grams twice per day (acts to release lipoprotein(a) from plaque formation and prevent further deposition of same).
  3. L-Lysine: 3 grams twice each day (acts to release lipoprotein(a) from plaque formation and prevent further deposition of same).
  4. Co-enzyme Q10: 90-180 mg. twice per day (strengthens the heart muscle).
  5. L-Carnitine: 3 grams twice per day (also strengthens the heart muscle).
  6. Niacin: Decreases production of lipoprotein(a) in the liver. Inositol hexanicotinate is a form of niacin which gives less of a problem with flushing and therefore allows for larger therapeutic doses. Begin with 250 mg. at lunch, 500 mg. at dinner and 500 mg. at bedtime the first day; then increase gradually over a few days until you reach four grams per day, or the highest dose under four grams you can tolerate. Be sure to ask your doctor for liver enzyme level tests every two months or less to be sure your liver is able to handle the dose you are taking.
  7. Vitamin E: 800-2400 IU per day. (Inhibits proliferation of smooth muscle cells in the walls of arteries undergoing the atherosclerotic changes.)