Case as follows:
A 2-year-old boy has brittle depigmented hair, cerebral atrophy, delayed myelination, motor delay, and mental retardation. Lysyl oxidase activity is decreased. The function of which of the following substances is most likely to be defective in this patient?
A) Albumin
B) Ceruloplasmin
C) Chondroitin sulfate
D) Collagen
Obviously the answer has to be collagen isn't it? One will ask so what's the diagnosis? Possible answer is Menkes Disease, which is an X-linked neurodegenerative disease of impaired copper transport. (obtained from http://emedicine.medscape.com/article/1180460-overview) It is also known as the kinky hair disease. The disease speaks for itself, kinky hair. Everything links to the defect of the collagen synthesis itself as well as the copper metabolism.
As an IMU student, we might think that copper metabolism? Isn't that something to do with Wilson's disease, better known as hepatolenticular degeneration in which there is autosomal recessive genetic disorder in which copper metabolism is affected and that copper builds up in the body. The most well known symptom is the Kayser-Fleischer rings which we always say when during our OSCE practice. We haven't seen one before so we don't know how it looks like. Other symptoms include neuropsychaitric symptoms, RTA, cardiomyopathy etc. One important thing about copper is that copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase. The main enzyme we are going to talk now is lysyl oxidase.
So what's so great about this enzyme? Lysyl? Something to do about collagen? Yes, absolutely. Collagen occurs in all multicellular animals and is the most abundant protein of vertebrates. It is a extracellular protein that is organised into insoluble fibers of great tensile strength. This suits collagens role as components of connective tissues such as bone, teeth, cartilage, tendon etc.(from Vishna' lecture note)
Mammals have at least 17 genetically distinct polypeptide chains (called chains) comprising 10 collagen variants as listed below:
Type Distribution
I Skin, bone, tendon, blood vessels andcornea
II Cartilage
III Blood vessels, foetal skin
IV Basement membrane
Collagen has a distinctive amino acid composition-nearly one third of its residues are Gly, another 15-30% are Proline, 4-hydroxyproline,and hydroxylysine. The hydroxylated residues appear only after collagen polypeptides are synthesised. The enzyme that converts Proline to Hydroxyproline is prolyl hydroxylase. Hyroxyproline is important as it confers stability upon collagen (intramolecular hydrogen bonds that may involve bridging water molecules). However, prolyl hydroxylase requires ascorbic acid (Vit C) to maintain its enzymatic activity. Thus for people with scurvy: skin lesions, blood vessels fragility, results because collagen cannot form fibres properly. This explains the importance of Vit C not only as an antioxidant itself but also a cofactor for prolyl hydroxylase in healthy growth of collagen in mammals. Reaction is as follows for prolyl hydroxylase:
Proline + α-ketoglutarate + O2 + Fe2+ → 4-hydroxyproline + Fe4+ + CO2 + succinate
One point which I want to point out in the case mentioned is the enzyme lysyl oxidase. A brief introduction of the enzyme by wikipedia:
Lysyl oxidase also known as protein-lysine 6-oxidase is a protein which in humans is encoded by the LOX gene. Its inhibition can cause lathyrism, but at the same time, its upregulation by tumor cells may promote metastasis of the existing tumor, causing it to become malignant and cancerous. Lysyl oxidase is an extracellular copper enzyme that catalyzes formation of aldehydes from lysine residues in collagen and elastin precursors.
This enzyme requires copper, therefore in any form of disease which impairs the synthesis of copper, it will result in this enzyme difficiency and the disease which can be resulted involves the as mentioned in the italic statement as well as the symptoms occuring in Menkes disease.The Menkes gene is located on the long arm of the X chromosome at Xq13.3, and the gene product (ATP7A) is a 1500–amino acid P-type adenosine triphosphatase (ATPase) that has 17 domains—6 copper binding, 8 transmembrane, a phosphatase, a phosphorylation, and an ATP binding.(from: http://emedicine.medscape.com/article/1180460-overview) This is the syndrome the boy is suffering from.
Another collagen disease is Ehlers-Danlos Syndrome. The famous one in which everyone see the clinical picture and say the condition is the Type I and II which have hypermobility of joint, skin hyperextensibility and wide atrophic scars. (from : http://emedicine.medscape.com/article/943567-overview) Type IV is the vascular one in which it is important to take note of and diagnose it as it will have disastrous consequences.
Type IV is the vascular/ecchymotic form. Patients with type IV Ehlers-Danlos syndrome have prominent venous markings, which are readily visible through the skin. Diagnostically, this type is most important because patients are subject to spontaneous rupture of the bowel, medium-sized arteries, or both. Often, rupture leads to early death. Median life expectancy in these patients is 45-50 years.
So that's about collagen for the while. I shall end this topic with collagen and aging.
Collagen and Aging
The sixth theory of aging is the Collagen Theory of Aging, This theory says that as we age, our collagen in our bodies gets older. When that happens the old collagen gets stiff and does not act as flexibly, causing problems, e.g., causes hypertension by not expanding to accomodate the flow of blood through the vessels, stiff collagen causes organs to malfunction as they seem to be "crispy" and hinder metabolic reactions.
