1. A. Synthesis of epinephrine from norepinephrineEpinephrine is synthesized through the transfer of a methyl group from the cofactor S-adenosylmethionine (SAM) to the amino group of norepinephrine. This reaction, shown in Figure 1 (see Figures section), takes place in a particular group of neurons in the brainstem and in adrenal medullary cells where the cytoplasmic enzyme PNMT or phenylethanolamine-N-methyltransferase is present and is able to catalyze epinephrine synthesis (Berg, Tymoczko, Stryer and Clarke, 2002; Ganong, 2001).B. Synthesis of acetylcholine from serineFigure 2 shows the conversion of the amino acid serine into phosphatidyl serine, then to phosphatidyl ethanolamine and after a series of methylation steps, into phosphatidylcholine, one of the more common phospholipids in animals. The liver enzyme phospholipase D catalyzes the metabolism of phosphatidylcholine into choline, a small amount of which is then absorbed into the bloodstream and is transported to the brain where acetyl coenzyme A helps to convert it to the neurotransmitter acetylcholine (Miller and Kelly, 1996).
C. Synthesis of creatine phosphate from arginine and glycineArginine and glycine in the kidney forms guanidoacetate, which in turn is methylated by S-adenosylmethionine in the liver to produce creatine. Creatine serves an important role in energy storage and release; creatine phosphokinase catalyzes the transfer of a phosphate group from ATP to form creatine phosphate, serving as storage for high energy phosphate molecules.
However, when there is a demand for energy, creatine phosphate readily releases the phosphate group for the conversion of ADP to ATP (King, 2006). The reaction scheme is shown in Figure 3.2. Conversion of homocysteine to methionine or cysteineFigure 4 shows the metabolism of methionine and homocysteine. Methionine is transmethylated to form homocysteine but can be regenerated through remethylation which is catalyzed by methionine synthase, with MTHF (5,10-methylenetetrahydrofolate) and vitamin B12 serving as cofactors in the reaction.
Homocysteine may also be irreversibly metabolized ultimately into cysteine through a transsulfuration reaction catalyzed by cystathionine-b-synthase (Chambers, Ueland, Wright, Doré, Refsum and Kooner (2001).3. HomocystinuriaHomocystinuria is a genetic metabolic disorder classically characterized by a deficiency in the enzyme cystathionine-b-synthase, although there are at least 7 other possible causes implicated, all of which lead to defective methionine/homocysteine metabolism. Since cystathionine-b-synthase catalyzes the conversion of homocysteine to cysteine, its absence leads to the accumulation of homocysteine (and methionine) in the serum and elevated levels in urine (Baloghova and Schwartz, 2006).The accumulation of homocysteine damages collagen and elastic fibers, hence the disease is characterized by a multisystemic disorder of connective tissues, muscles, and central nervous and cardiovascular systems. Likewise, elevated levels of methionine have been known to cause neurotoxic effects (Baloghova and Schwartz, 2006). Some of the common symptoms of the disease therefore include a tall, thin build, long limbs, high-arched feet, knock-knees, pectus excavatum (funnel chest; chest has a caved-in or sunken appearance), pectus carinatum (pigeon breast; having a protrusion over the sternum), nearsightedness, mental retardation and psychiatric disease (Medline Plus Medical Encyclopedia, 2006).
Homocystinuria shares several clinical features with Marfan syndrome, a genetic disorder affecting connective tissues (Medline Plus Medical Encyclopedia, 2006). However, mental retardation, psychiatric disorders and elevated homocysteine urine levels are not observed in Marfan syndrome patients and hence serve to distinguish between the two (Baloghova and Schwartz, 2006).Complications that may arise from homocystinuria include pancreatitis and thromboembolic complications such as blood clots. No specific treatment has yet been established for homocystinuria and records show that nearly one out of four patients die before the age of thirty. However, many patients still show favorable prognosis given that their diets are closely monitored and that they are given adequate medication to supplement their deficiencies (Baloghova and Schwartz, 2006; Medline Plus Medical Encyclopedia, 2006).Cystathioninuria Cystathioninuria is a disorder characterized by a deficiency in cystathionase, the enzyme that converts cystathionine to cysteine.
As a result of the deficiency, cystathionine accumulates in the plasma and levels become elevated in urine but aside from this, the disorder does not exhibit prominent clinical signs and symptoms (Merck Manuals Online Medical Library, 2005). Cystathioninuria has been associated with a wide variety of diseases but due to observed inconsistencies it has been considered rather to be a “benign biochemical anomaly” (Amberger and Przylepa, 2003).Examples of symptoms and clinical signs that have been observed in the first reported cases of the disorder include developmental defects about the ears and feet, thrombocytopenia and urinary lithiasis.
Although some of the patients that have been diagnosed with cystathioninuria also suffered from mental retardation, Perry et. al, some of the first scientists who reported cytathioninuria cases, believe that the association of the disorder to mental defects and other disorders may have simply been coincidental. Two other authors, Whelan and Scriver, likewise believe that cystathioninuria is plainly a benign genetic anomaly (in Amberger and Przylepa, 2003).
A 1965 study by Frimpter has found that in cystathioninuria, cystathionase is defective in that it is unable to bind to its coenzyme, pyridoxal phosphate. Results from in vitro studies indicated that high doses of pyridoxine might prove to be of therapeutic use (in Amberger and Przylepa, 2003). Figures References:Amberger, J.S. & Przylepa, K.A. (2003).
#219500 Cystathioninuria. Retrieved May 20, 2007, from the Online Mendelian Inheritance in Man Database.Baloghova, J., & Schwartz, R.
A. (2006). Homocystinuria. Retrieved May 20, 2007, from eMedicine on http://www.emedicine.com/derm/topic708.
htmBerg , J. M., Tymoczko , J. L., Stryer, L.
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Biochemistry, 5th ed. New York, NY: W. H.
Freeman and Company.Chambers, J. C., Ueland, P. M., Wright, M., Doré, C.
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S. (2001). Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects. Circulation Research, 89(2), 187-192.Editors of the Merck Manuals Online Medical Library. (2005). Amino acid and organic acid metabolism disorders.
Merck Manuals Online Medical Library. Retrieved May 20, 2007, from http://www.merck.com/mmpe/sec19/ch296/ch296c.htmlGanong, W. F. (2001).
Review of Medical Physiology, 20th ed. USA: McGraw-Hill Medical Publishing Division.King, M. W.
(2006). The medical biochemistry page: Amino acid derivatives. Retrieved May 20, 2007, from http://web.
indstate.edu/thcme/mwking/aminoacidderivatives.htmlMedline Plus Medical Encyclopedia. (2006). Homocystinuria. Retrieved May 20, 2007, from http://www.
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