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MechanismMechanism
The side-chain amino group of Orn attacks the carbonyl carbon of CP nucleophilically, to form a tetrahedral transition state, found in the middle. A Charge rearrangement then releases Cit and Pi.
N5-Phosphonoacetyl-l-ornithine (PALO, 1) is a bisubstrate transition-state analog which competitively inhibits ornithine transcarbamylase (OTC) in vitro. ( https://www.google.com/#hl=en&sugexp=les%3B&gs_nf=3&gs_mss=Ornithine%20transcarbamylase%20in&tok=0eueaC5bjGY4yeUuw3p3dg&pq=ornithine%20transcarbamylase&cp=37&gs_id=30d&xhr=t&q=Ornithine%20transcarbamylase%20inhibitors&pf=p&safe=off&tbo=d&sclient=psy-ab&oq=Ornithine+transcarbamylase+inhibitors&gs_l=&pbx=1&bav=on.2,or.r_gc.r_pw.r_qf.&fp=689574a48716d7d0&bpcl=38093640&biw=1152&bih=499)
Studies have also shown that N δ-(N′-sulfodiaminophosphinyl)-l-ornithine (PSOrn), with its three unique N-P bonds, represents a true transition state analogue for ornithine transcarbamoylases (OTC)(http://www.jbc.org/content/275/26/20012). Another inhibitor being studied is The inhibition of ornithine transcarbamoylase from Escherichia coli W by phaseolotoxin. In the presence of phaseolotoxin ornithine transcarbamoylase exhibited a transient phase of activity before a steady state. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1144443/)
ImplicationsImplications
Ornithine transcarbamylase deficiency (OTCD)
If a person is deficient in OTC, ammonia levels will build up, and this will cause neurological problems. Levels of the amino acids glutamate and alanine will be increased (as these are the amino acids that receive nitrogen from others).
Levels of urea cycle intermediates may be decreased, as carbamoyl phosphate cannot replenish the cycle. The carbamoyl phosphate instead goes into the uridine monophosphate synthetic pathway. Here orotic acid (one step of this alternative pathway) levels in the blood are increased.
A potential treatment for the high ammonia levels is to give sodium benzoate, which combines with glycine to produce hippurate, at the same time removing an ammonium group. Biotin also plays an important role in the functioning of the OTC enzyme [1] and has been shown to reduce ammonia intoxication in animal experiment.
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