Metabolic Cross-linkage

Metabolic cross-linkage is a term used to describe 2 main processes: glycation and carbonylation. Both chemical processes are very powerful destructive metabolic processes that can result in chronic disorders formation and advances aging

Glycation

The abundance of glucose in the blood due to internal causes (e.g. diabetes), or external causes (High refined sugar consumption), will Auto-oxidized” and Spontaneouslystarts to from cross linkage between sugars and the body’s proteins such as collagen and keratin, a process known as “Glycation”; this process will result in the formation of highly-active free radicals known as “Advanced Glycation End products” (AGEs); when the same process occurs with lipid, “Advanced Lipoxation End products” (ALEs) produces (Lipid peroxidation)

AGEs stimulate inflammatory responses and, in this way, people with diabetes and refined sugar intake develop high levels of inflammation (Hyperoxidative sugar stress theory).When glycation affects collagen-rich subcutaneous and periarticular connective tissues, such as tendon, ligament, fascia, and joint capsule; the end result, degeneration and skeletal changes of the joints and intervertebral discs; in diabetics, this will results in “Diabetic rheumatism

Glycation and lipoxation causes the formation of “Defective” cellular proteins and lipids; once cellular proteins or lipids are cross-linked, they become “Severely-degraded” and “Non-functional”. These AGEs and ALEs spark the metabolic pathway of “Inflammation”, resulting in “Chronic, low-grade, chronic inflammation”. The body proteins that are vulnerable to AGEs and ALEs are the proteins of the: nerves, blood vessels lining, retina, and kidneys

Carbonylation

When the body fails to detoxify free radicals due to overproduction from a pathological process, these free radicals will start to add molecular oxygen to “Polyunsaturated fatty acids”, typically found in cellular membrane; this oxygen addition will result in the formation of oxidized fatty acids known as “Hydroperoxy fatty acids(Lipid peroxidation), which will spontaneously degrade into small, diffusible, carbonyl-containing lipids (α,β-unsaturated aldehydes) 

When a lipid aldehyde is added to a protein, it will add its carbonyl group (R-C=O) to the protein structure, resulting in a defective protein known as “Protein carbonylation

Carbonylation is the origin of “Browning” of food, such as the browning of a roasted chicken. Carbonylated proteins simply mean “Proteins oxidation”. Carbonylation is responsible for up to 30% body tissues damage as we age    

Examples of amino-acids typically affected by carbonylation: proline & lysine (Vascular endothelium), histidine (Kidney), cystine (Glutathione)

Diseases associated with protein carbonyaltion include: diabetes mellitus, chronic renal failure (71% carbonylation of proteinuria), albumin carbonylation & toxicity, amyotrophic lateral sclerosis, Alzheimer’s & Parkinson’s diseases, chronic lung disease neuropathies, systemic amyloidosis, and psoariasis

 

Selected references

1. Ruskovska T et al. Oxidative stress and protein carbonylation in adipose tissue — Implications for insulin resistance and diabetes mellitus. Journal of Proteomics 2013; 92: 323-334

2. Curtis JM et al. Protein carbonylation and metabolic control systems. Trends in Endocrinology & Metabolism 2012; 23(8): 399-406

3. Dalle-Donne I et al. Protein carbonylation in human diseases. Trends in Molecular Medicine2003; 9(4): 169-176