Histidine Synthesis: An Overview of Research

Histidine Synthesis An Overview of ResearchHistidine SynthesisKathryn McC anyister The piece of work of the biosynthetic steel tract jumper lead to synthesis of the amino acid histidine in prokaryotes and lower eukaryotes was begun much than 40 years ago and has resulted in the unraveling of m some(prenominal) an new(prenominal)(prenominal) fundamental mechanisms of biology (1). With this it faeces be assumed that much of the high appearance is whapn or is in the process of becoming known. What is to be talk overed is the parcel of land itself, which has been studied extensively in E. coli and S. typhimurium. plot of land many may not consider wherefore this road is most-valuable in the clay it should not be understated that this is a precise fundamental avenue. Histidine is an inherent amino acid. Histidine metabolism has been extensively researched and many articles amaze been published about the numerous effects of having deficient or excessive histidine in the blood. This paper will go over the head for the hills of the pathway in detail from the beginning to the end result, Histidine. Histidine is something that is really primal in the human body and this will be revealed later in the paper. today the portion of the pathway to be discussed is the portion in which Histidine is do into Carnosine. Now in order to discuss this portion of the pathway we must(prenominal) first find out how we make Histidine in the first place. This pathway to a fault occurs in prokaryotes which be the main organism in which this pathway has been studied. The disease that we will be focusing on is Carnosinemia. This disease is caused by a deficient amount of histidine in the body. Lastly we will discuss the prevalence of this disease in society and how this could potentially affect the population in the future.The histidine system is an important system in the body. It has also helped with some other theories. The histidine system was of the utmost importance in the definition and refinement of the operon system (1). In order to understand this guess you first must understand what an operon is. An operon contains a group of genes that code for enzymes call ford in a metabolous pathway (2). This is very important in the processes of the organism. The operon helps the cell con table service energy. The operon theory was first proposed by the French microbiologist Franois Jacob and Jacques Monod in the early 1960s (2). While this fronts irrelevant in fact, it has been calculated that 41 ATP molecules are sacrificed for separately histidine molecule make (1). With that kind of energy needed its no wonder that the majority of Histidine comes from diet. Histidine is a costly amino acid to produce, so in order for the body to maintain itself it has to be able to gull Histidine from the food in which we eat. If enough of this amino acid is not taken in at that placefore it could potentially cause problems.Histidine is one of the most important substances in the body only because it can be converted into other things one of which is really important in the body, haemoglobin. Furthermore, it is involved in unhomogeneous metabolic receptions and hence ensures indirectly the oxygen supply to all the organs and tissues (3). Without oxygen the body would tied(p)tually begin to shut down.In particular, in the well-known yeast S. cerevisiae, the seven genes liable for the biosynthesis of histidine are find on six different chromosomes (1). Now this is very different than in Archaebacteria. The his genes in archaebacterial are less well known than in eubacterium only three his genes nonplus been recognized in just quaternary species, three of them belonging to the genus Methanococcus and one to Halobacterium (1). This is interesting since there are seven genes.The demonstration that hisI and hisE is, in fact, a single gene (now hisI) brought the genes to eighter and the steps to 10 (1). Quickly coverin g these steps is no halcyon task, plainly below is an attempt to do so. The first reaction in histidine biosynthesis is the condensing of ATP and 5-phophoribosyl 1-pyro inorganic phosphate (PRPP) to form N-5-phosphoribosyl-ATP (PRATP) (1). This tell apart reaction is involved in feedback inhibition. The second step in histidine biosynthesis is the condensation of PRATP into PRAMP. From PRAMP the synthesis produces BBMII. The fourth step of the pathway is an internal redox reaction, also known as Amadori rearrangement, involving the isomerization of the aminoaldose 5-ProFAR to the aminoketose N-(5-phosphoribulosyl)-formimino-5-aminoimidazole-4-carboxamide-ribonucleotide (5-PRFAR or BBMIII) (1). This is then synthesized into imidazole-glycerol-phosphate, also known as IGP.AICAR, which is produced in the reaction catalyzed by the IGP synthase, is recycled into the de novo p piss biosynthetic pathway (1).From there it is dehydrated and the resulting enol is ketonized nonenzymatically to imidazole-acetol-phosphate (IAP) (1). The seventh step of this pathway is a reversible one in which IAP is involved. The reaction leads to the production of -ketoglutarate and L-histidinol-phosphate (HOL-P) (1). From there it loses the phosphate and becomes L-histidinol (HOL). HOL is oxidized and becomes L-histidinal, which is an unstable portion of the pathway. From there it proceeds to histidine by way of a transferase, or in other words it moves the intermediate to other site on the chain. Nevertheless, the two initial substrates of histidine biosynthesis, PRPP and ATP, play a key role in intermediate and energetic metabolism and link this pathway to the biosynthesis of purines, pyrimidines, pyridine nucleotide, folates, and tryptophan (1).Klem and Davisson found that the protein encoded by the hisF gene has an ammoni-dependent activity that is responsible for the conversion of PRFAR to AICAR and IFP, while the product of the hisH gene had no detectable catalytic properties. However, in combination, the two proteins were able to carry out the reaction in the presence of glutamine as a nitrogen donor without releasing any free metabolic intermediate (1). Final identification was generally achieved from desoxyribonucleic acid and protein sequence comparison with the E. coli counterparts, assuming, as it is widely accepted, the the biosynthetic pathway is fundamentally the same in all organisms (1).This later may be associated with dietary instruments, since it is known that histidinuria may be present after a heavily protein meal especially in children it is also increased during pregnancy and at the beginning of the luteal phase of the menstrual cycle (9). This is interesting to preeminence because this body of work was done in 1962 ns was based on a urine analysis of the mentally defective population of Northern Ireland. This study proposed that there were approximately 4,000 people under the care of the Northern Ireland Hospitals Authority during this study. In the 2,081 urines examined there were two baptistrys of very severe generalized aminoaciduria and 36 efforts of castigate severity these latter are of central cluster pattern involving glycine, serine, alanine, glutamine and/or glutamic acid, histidine, threonine and sometimes taurine (9). While these way outs may seem peanut when you take that throughout the whole population who may not know that they have a wish, the numbers translate to 1.8% of the population. It is appreciated that many of the supra amino-acidurias may have a metabolic basis quite unrelated to mental retardation, and it is hoped to study these cases in detail (9). This is later confirmed by further testing.The portion of the pathway that will be discussed is from Histidine to Carnosine. This may seem unrelated but Carnosinemia is caused by a lack of Histidine because it is partially made up of Histidine. Without Histidine there can be no Carnosine made. One of the genes that have recently been linked to diabetic nephropathy is Carnosine dipeptidase-1 (6). This is just one of the problems that carnosinemia could potentially cause in the human body. In humans, circulating Carnosine is readily lush by the highly active serum carnosinase enzyme, which is secreted from the liver into the plasma (6). Without Carnosine this enzyme isnt able to function properly. Carnosinase is a true dipeptidase and this was discovered in an sample that was published in 1985. Human tissue carnosinase (EC 3.4.13.3) had optimum activity at pH 9.5 and was a cysteine peptidase, being activated by dithiothreitol and inhibited by p-hydroxymercuribenzoate (7). While pH may be manipulated in a lab, our body adjusts our pH everyday on a cellular level in order to work at maximum capacity at all times.Carnosine could hold the potential to protect type 2 diabetics from some of the complications associated with nerve damage. From these genetic data in human patients, it was hypothesized that L-Carnosine serum levels are associated with the risk of infection for late complications of diabetic disease and that L-Carnosine acts as a cautionary factor (6). This is interesting to note since most symptoms associated with low amino acid levels involve some sort of nerve problem. The researchers hypothesized that L-Carnosine may be a protective factor when it comes to diabetic patients and their potential nerve problems associated with type 2 diabetes. In the results they found that mice that were supplemented with L-Carnosine had later onset diabetes and was much milder than anticipated. Their conclusion was that hCN1-dependent susceptibility to diabetic nephropathy may at least in part be mediated by altered glucose metabolism in type 2 diabetic patients (6).It has been found that Carnosine not only protects against type 2 diabetes but also with LDL and high cholesterin. In an experiment published in 2007 it was found that Carnosine was able to lower LDL without the dangerous accumulat ion of cholesterin that many drugs on the market cause. The key finding of the current study is that Carnosine and its constituents are effective at equimolar concentrations to the modifying agent, out data suggests that Carnosine and its constituents may serve as effective scavengers of carbonyl compounds and inhibitors of protein glycation in vivo, and as potential curative agents to inhibit diabetes-induced atherosclerosis. (5).That is why Carnosine is so important in the human body. Now managing this disease isnt as simple as just ingesting more histidine or Carnosine. There is no known cure for carnosinemia. They are suave trying to figure out what causes carnosinemia. The signs and symptoms of carnosinemia are aminoaciduria, cognitive impairment, developmental regress, encephalogram abnormality, seizures, autosomal recessive inheritance, carnosinuria, generalized myoclonic seizures, and intellectual disability (12). Most of the symptoms as stated have to do with the brain a nd its functions, and this is very similar to a number of other diseases that have to do with amino acid deficiency. alas as stated there is no known cure or management for this disease. Unfortunately only about 30 cases have been inform to date so not a lot of people even know that this disease exists.So far, all genetically determined diseases payable to primarily to an enzyme deficiency are inherited by recessive or sex-linked mechanisms and this rule is holding so well that there is bantam reason to search for such a cause in conditions demo dominant inheritance (4). Carnosinemia is an autosomal recessive disorder, meaning that both parents have to be carriers in order for the child to be effected. The commonest approach has been to go forth a diet deprived of an offending constituent, the greatest experience having been obtained with the intercession by this means of phenylketonuria and galactosaemia (4). When researched no known treatment could be neither found, nor any experimental treatments for this disease. Not enough people run across from this disease to make experimentation worthwhile for scientists. Dietary restriction is by no means the only approach to therapy and in disorders of many essential amino-acids may not even be feasible (4). Such is the case for carnosinemia and histidine deficiency.In conclusion, the study of histidine has spanned more than 40 years and is still very much ongoing. The two main study specimens that have been used to study the Histidine pathway are E. coli and S. typhimurium. The pathway is comprised of 10 steps in which it starts at ATP and ends with Histidine. From there is can be transformed into a number of different compounds including Histamine and Haemoglobin. There are seven genes that make up the Histidine pathway and they are located on six different chromosomes in eukaryotes. Histidine stirring is mostly dietary because it is so costly for the body to make it. Which is why Histidinuria is found esp ecially in children and pregnant women. They also found the Histidine deficiency can cause many developmental delays, and was found in a some of the mentally challenged people tested in Northern Ireland. Histidine makes up Carnosine in the human body which is very important for those with diabetes. It has been found that Carnosine may have a protective factor for those with type 2 diabetes. It may prevent those with type 2 diabetes from developing a severe case of nephropathy. It was also found to help lower LDL without causing cholesterol buildup like some of the drugs on the market today. This is why Carnosine is so important in the human body. Carnosinemia is a very serious disease and there is no known cure or treatment for it. The symptoms of Carnosinemia range from cognitive impairment to seizures. Unfortunately this disease cant be headstrong with diet, and there are no known medications or treatments for this disease. Carnosinemia is a very serious disease caused by a defic iency of Histidine.ReferencesAlifano, P. Fani, R Li, P. Lazcano, A. Bazzicalupo, M. Carlomagno, M. S. Bruni, C.B. Histidine Biosynthetic Pathway and Genes Structure, Regulation, and Evolution. Am. Soc. For Microbiology. 1996, Vol. 60, 44-69.Encyclopedia Britannica. Operon. http//www.britannica.com/EBchecked/topic/429974/operon (accessed Nov 25, 2014).Amino Acid Studies. L-histidine. http//aminoacidstudies.org/l-histidine/ (accessed Nov 25, 2014).Raine, D. 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