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The Master Corrosive: Homo-Cysteine, the Evil 21st Amino Acid
Proteins are folded chains of 20 different amino acids.  The sulfur in one of them, cysteine, does most of the shape and function giving.  On the other hand, a very similar amino acid, homo-cysteine, is a toxin that we continuously produce-and must deal with.  It degrades cysteine-based structure and more.  It can only be lowered to safe levels by several B vitamins.  'Healthy' cysteine is fundamental to prevent protein aging, and as goes the expression, all roads (of research) lead to Rome, ironically, home of the 'Cysteine' chapel.  Making things worse, homocysteine also damages amino acid lysine, another structural center pin in collagen and elastin structure in artery, heart, bone and skin.

  Sulfur vulcanizes liquid latex into the structure of rubber and sulfur has the same shape-giving role in our proteins and where it is part of the 3-carbon cysteine, made from the 4-carbon homocysteine, itself only made from the 5-carbon essential amino acid methionine [thio means sulfur, meth means a 1-carbon atom group like methane, natural gas, and -ine stands for protein, nitrogen or amino, like ammonia].

Requiring most B-vitamins, the '4' is recycled back into methionine or turned into 3-carbon cysteineHomocysteine is even more toxic when it forms a high-energy 'Evil Ring', a 'Lethal Lactone' looking for proteins to corrode with its sulfur and oxygen, opening at x-x in the picture.  If homocysteine would 'thiolate' a protein that lives about 1 hour like insulin, with 6 cysteines forming 3 sulfur 'bridges', we'd simply make new.   When it corrodes the protein of LDL-cholesterol droplets that lives 2.5 days, things get serious.  Homocysteine makes LDL a Trojan horse and affects its function.  However, if corrosion is to a life-long protein with 380 cysteines like fibrillin, the damage can be artery fatal, as in Marfan syndrome and homo-cysteine-uria.

Because 'straight' homocysteine can fold back onto itself, if it would wind up in a protein during synthesis it could cleave the protein.  Thus, it is removed .. but in that reactive ring shape --doing damage, 'thiolating', in the cell and in its surrounding structure.  The fewer B vitamins in your diet, the more lactone!

So, what's to corrode in an artery?
Well, I like to think of arteries as a thick multi-layer of muscle cells sandwiched between 2 structural layers.  Through the outside layer come 300 capillaries per square millimeter feeding the central muscle cells.  On the inside is a cell-hostile layer of just structure.  There are basically 3 materials: collagen, elastin with its fibers (about 18, all proteins) and proteo-glycans (stuff also found in cartilage).  Here it gets interesting.  Some of these 3 structural families can be life-long and all are corroded, poorly made or poorly repaired in the presence of that 'Evil sulfur ring'.  The 3 structural families are:

  1. Collagen, bundles of 3-strand rope stronger than nylon of which the ends are kept from unraveling by cysteine sulfur 'bridges' during assembly.  The ropes are then interconnected by 3-armed pyridinoline (see picture) that cannot be made when homocysteine has destroyed the 'knitting machine' (lysyl-oxidase) that finally makes tissue out of rope.  Copper and vitamins B6 and C are also essential.  In bone, calcium builds along this rope, in artery the rope keeps it from ballooning under pressure.  Collagen without shape is gelatin.

   2. Elastin, an amazing 'rubber' NOT vulcanized by sulfur but by the above mentioned lysyl-oxidase but that, here, in elastin, forms 4-armed 'desmosine' cross-links.  Again: high homocysteine, insufficient copper or vitamins B6 (most people) or C, no bridges.  This stuff is so tough, it survives a week-long bath in hot acid or alkaline.  It is secreted and then assembled into life-long 'apartments' by the fragile muscle cells, protecting them in multi layer (laminae) rooms with windows (fenestrations) and elastin frames and curtains.  Without such 'happy homes' muscle cells may wander into the inside layer of the artery where they, and the artery owner, come to grief.  While collagen may live for years (less than 1 year in heart), elastin's half-life is an astounding 70 years. The bad news is that the other half has to be maintained, or made anew.

   3. Proteo-glycans, a family of water filled 'compressive' and 'chemical storage' molecules of arteries and joint cartilage.  It has 'di-cysteine' sulfur bridges in a 'core-protein', and bottle brush like arms made from glucosamine and chondroitin sulfates.  That is the stuff that works for joint pain and repair.  Homocysteine can damage the protein and add excess sulfate to the glycan (sugar-like) arms, affecting function and making it attract LDL droplets that should not be there.

Lowering homo-cysteine
When methionine donates its 1-carbon methyl group [-CH3] to one of about 100 enzymes (protein machines), it turns into that temporary toxin.  Strategies :

First, eat foods with methyls, like eggs, liver, soybean lecithin and foods with betaine (tri-methyl-glycine, TMG) such as wheat bran, germ and spinach.  Such 'high choline' foods (including beans, rice, peas, lentils) supply methyl for methionine's vital roles.  Insufficient (B-vitamin regenerated) methionine and your DNA looks like if radiated by X-rays, says Bruce Ames.  Think: cancer, birth and pregnancy problems (spine, harelip, clubfoot, preeclampsia, severe heart defects, other).

Second, subtract one carbon to make cysteine for which many of us need 3 to 15x more vitamin B-6 than average intakes, or about 5 - 25 mg/d.  No B-6 and atherosclerosis is quick and massive (picture).  Alternatively, add one carbon to re-generate methionine with betaine (see above; 2-5 g/day) or with vitamin B12 plus folic acid and here, without both, nothing happens and homocysteine sky rockets. Magnesium, copper, zinc and vitamin B2 also help reduce corrosive homocysteine.  Sadly, the best 'well balanced' diet has insufficient amounts of most actors.

Third, coffee (sorry), smoking, mental stress, high-dose niacin (to raise the 'happy' HDL-cholesterol) and drugs like fibrate and methotrexate raise homocysteineIn each case a multi-vitamin as described here reverses that corrosive increase.

Know your homo-cysteine
Most heart disease, stroke, macular degeneration, cancer, Alzheimer's, joint and bone disease (fracture) does not happen when your life-long homocysteine is near SIX [6 Ámol/L].  This theory of healthy aging has not been proven wrong and unites all roads of research.  When all road signs read Rome, it may be wise to heed their advice.  When your car or proteins are damaged by corrosion, can a 'car'diologist, blood pressure or cholesterol drug really restore youth?

That magic number SIX is found in 15 year old U.S. men and 22 year old women after folic acid was added to the flour supply.  Homocysteine was '22' in over 90 year olds near Boston and in 24 year olds in New Delhi where the common foods have essentially no folic acid and vitamin B12.  Seven cents per year would add folic acid, B12 and vitamin B6 to the flour supply.  This would drop homocysteine by half.  Instead, a monumental heart disease epidemic in India and other countries where micro-nutrients are under supplied is under way.  Massive and early in life!  Highest rate heart disease Pakistan is a prime example.  Less than $0.50 per year is the world-price to replenish required amounts of most micro-nutrients.  Scientists debate and politicians don't act while Rome burns!

It's 'genetic' is a way for experts to tell you they don't know, and genes can't explain epidemics anyhow, but in homocysteine genes do play roles in about 10% of us.  Women have life-long exposure to homocysteine 10-15% below men and get heart attacks 10 years later in life.  You can't change your genes or gender and may never know your homocysteine level so taking a high 'potency' multi-vitamin + mineral supplement is brilliant prevention, even helping 'bad genes' and leveling the gender gap for men.  Such 'anti-rust' vitamins slowly repair existing damage resulting in 25% fewer strokes.  Also, fewer bone fractures, from better collagen, and proably less macular degeneration.  The latest: Stopping brain shrinkage with age.  Nutrients nourish reactions, drugs block them.  When homocysteine is over 'six' (maybe seven), you're under nourished for your genes and long-term health.

Our other defenses against homo-cysteine
Our defenses: first, we sacrifice about 20 grams per day of blood proteins that bind homocysteine, albumin and hemoglobin.  Next, our blood has about 1/2 a gram of "PON".  Like its sister protein BLH, but that works within the cell, PON detoxifies the 'lethal lactone' formed whenever cells make proteins in the presence of homocysteine.  PON travels outside the cell attached to the happy HDL-(good)cholesterol protein, and when PON works well, about half the mortality!

Homo-cysteine is not alone
Homocysteine corrosion starts early and targets sulfur in proteins as well as the 'free' amino of their lysine.  Excess blood sugar in diabetes also generates toxins attacking lysine as well as arginine, another component vital for protein structure and function.  One such toxin is glyoxal (C2H2O2), also made by frying temperatures.  Now we have two types of corrosives teaming up to destroy proteins in arteries, capillaries and finally organs and bone.  While homocysteine is controllable by B-vitamins, blood sugar is made from sugars and starch and the more rapidly they are released from refined or cooked foods, the worse diabetic control becomes.  In diabetes, a measure of sugar protein damage is 'glycated' hemoglobin called HbA1c.  When proteins are degraded by thiolation and glycation, so is their owner.  Damage prevention is key since repair is never easy.  The story is more complex but these are the basics!

Homo sapiens is alone
Men is alone in the animal kingdom using fire and electricity--and naturally getting athero-sclerosis.  We poison rabbits with cholesterol and remove genes from mice to make 'mouse models' to study what anyone near a food store does 'naturally'.  Big fish eat little fish raw and whole; people deep fry fish fillets. Comparable animals get 3x the B vitamins we get from even the best diets.   For starters, anything we do to food destroys folic acid and B6, anything.  U.S. heart deaths started dropping when vitamins were added to breakfast cereals in the 1960's and the decline trippled after 1998 when folic acid fortification became mandatory; more so in stroke deaths.  A high dose multi-vitamin/mineral brings man back to the micro-nutrient levels of our animal cousins, and the levels our genome evidently developed on.  Add omega-3 oils (canola-rapeseed, fish oil pills) and some magnesium and (often) vitamin D, and long-term heart health may become a reality
Page as PDFPictures and more of the science.  With thanks by yours truly to Drs. Genest, Kauffman, McCully & Rose (2020-1-1).

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