Histidine-ammonia lyase

The first step in the biological degradation of histidine is formation of a 4-methylideneimidazol-5-one (MIO) by cyclization of a segment of the peptide chain in the histidine ammonia lyase enzyme. Propose a mechanism. 

A specialized amino acid residue that serves as an essesn-tial electrophilic center in several enzymatic reactions, including those catalyzed by L-phenylalanine ammonia lyase (Reaction L-phenylalanine tranx-cinnamate + NH3) and L-histidine ammonia lyase (Reaction L-histi-dine urocanate + NH3). The former facilitates the elimination of ammonia and the pro-S hydrogen of phe-nylanine, and the initial step is nucleophilic attack of... 

HISTAMINE N-METHYLTRANSFERASE HISTIDINE AMMONIA-LYASE DEHYDROALANINE HISTIDINE DECARBOXYLASE Histidine decarboxylase reduction, BOROHYDRIDE REDUCTION HISTIDINOL DEHYDROGENASE... 

The enzyme responsible for this reaction is histidine ammonia lyase or bistidase. 

Considerable progress has been made with elucidating the functional aspects of the PAL protein, assisted by the availability of the crystal structure for histidine ammonia lyase (HAL), which catalyzes a reaction similar to that of PAL, the conversion of L-histidine to... 

FIGURE 18-26 Catabolic pathways for arginine, histidine, glutamate, glutamine, and proline. These amino acids are converted to a-ketoglutarate. The numbered steps in the histidine pathway are catalyzed by histidine ammonia lyase, urocanate hydratase, imida-zolonepropionase, and glutamate formimino transferase. 

Catabolism of histidine in most organisms proceeds via an initial elimination of NH3 to form urocanic acid (Eq. 14-44). The absence of the enzyme L-histidine ammonia-lyase (histidase) causes the genetic disease histidinemia 284/285 A similar reaction is catalyzed by the important plant enzyme L-phenylalanine ammonia-lyase. It eliminates -NH3+ along with the pro-S hydrogen in the (3 position of phenylalanine to form frans-cinnamate (Eq. 14-45). Tyrosine is converted to p-coumarate by the same enzyme. Cinnamate and coumarate are formed in higher plants and are converted into a vast array of derivatives (Box 21-E,... 

Nevertheless, malonyl-CoA is a major metabolite. It is an intermediate in fatty acid synthesis (see Fig. 17-12) and is formed in the peroxisomal P oxidation of odd chain-length dicarboxylic acids.703 Excess malonyl-CoA is decarboxylated in peroxisomes, and lack of the decarboxylase enzyme in mammals causes the lethal malonic aciduria.703 Some propionyl-CoA may also be metabolized by this pathway. The modified P oxidation sequence indicated on the left side of Fig. 17-3 is used in green plants and in many microorganisms. 3-Hydroxypropionyl-CoA is hydrolyzed to free P-hydroxypropionate, which is then oxidized to malonic semialdehyde and converted to acetyl-CoA by reactions that have not been completely described. Another possible pathway of propionate metabolism is the direct conversion to pyruvate via a oxidation into lactate, a mechanism that may be employed by some bacteria. Another route to lactate is through addition of water to acrylyl-CoA, the product of step a of Fig. 17-3. Tire water molecule adds in the "wrong way," the OH ion going to the a carbon instead of the P (Eq. 17-8). An enzyme with an active site similar to that of histidine ammonia-lyase (Eq. 14-48) could... 

A large number of a, 3-didehydro-a-amino acids have been identified as constituents of relatively low molecular weight cyclic compounds from microbial sources. However, the presence of a,p-didehydroalanine in bacterial as well as in mammalian histidine ammonia lyase and in phenylalanine ammonia lyase shows that the occurrence of a,p-didehydro-a-amino acids is not limited to small molecules alone 8 These residues are incorporated in natural sequences by posttranslation modification. a,p-Didehydro-a-amino acids have also been postulated to be precursors in the biosynthesis of several heterocyclic metabolites including penicillin and cephalosporin 9 Other well-known compounds containing ,( -di-dehydro-a-amino acids are nisin 10,11 (a food preservative112 ), subtilin (a broad spectrum antibiotic) 13 and some of the metabolites isolated from Streptomyces strains such as gri-seoviridin 14 ... 

R.R. Walters, P.A. Johnson and R.P. Buck, Histidine ammonia-lyase enzyme electrode for determination of L-histidine, Anal. Chem., 52 (1980) 1684-1690. 

Scott, I.R. Factors controlling the expressed activity of histidine ammonia lyase in the epidermis and the resulting accumulation of urocanic acid, Biochem. J., 194, 829, 1981. 

Presently, some information is available on the structure of the active site of PAL and its mechanism of action. This knowledge was advanced with an aim of studies on PAL mutants obtained by site-directed mutagenesis, 100-102 comparison of its structure with the recently determined three-dimensional structure of histidine ammonia-lyase io3,i°4 as wejj as (fog detailed analysis of structure-activity relationship found for its inhibitors.105-108 Despite a recent knowledge of PAL three-dimensional structure, 109 110 the detailed mechanism of this particular enzyme action remains unresolved. 

M Baedeker, G E Schulz (2002) Structures of two histidine ammonia-lyase modifications and implications for the catalytic mechanism Eur J Biochem 269(6) 1790-1797... 

T F Schwede, J Retey, G E Schulz (1999) Crystal structure of histidine ammonia-lyase revealing a novel polypeptide modification as the catalytic electrophile Biochemistry 38(17) 5355-5361... 

Because of the high selectivity and sensitivity of the postcolumn fluorescence detection of histidine with OPA, the present HPLC method is applicable to a specific and rapid assay of histidine in human semm, blood, and urine after simple pretreatment. A recent paper demonstrated that the postcolumn detection with OPA was applicable to the simultaneous assays of histidine and its major metabolites cis- and frawi-urocanic acids) in human stratum corneum. " The postcolumn detection system was also applicable to the flow injection analysis (FIA) method for the assay of histidine in semm and urine. The FIA method enabled us to determine histidine in blood after pretreatment of the sample with A-ethylmaleimide (masking reagent of glutathione).These methods are useful in the diagnosis of histidinanemia, one of hereditary metabolic disorders characterized by a virtual deficiency of histidine ammonia-lyase. 

Histidinemia 235800 Histidine ammonia lyase. >1 25,000 Mental retardation, speech delay,. . possible ascertainment bias. /... 

Histidinemia results from deficiency of histidine ammonia-lyase. With a normal diet, histidine (and the products imidazole-pyruvate, imidazole-lactate, imidazole-acetate) accumulates in plasma, cerebrospinal fluid, and urine. This rare autosomal recessive disease may be benign or may manifest with mental retardation and speech defects. 

Histidine ammonia lyase (HAL, histidinase, histidine-a-deaminase, E.C. 4.3.1.3) is capable of abstracting ammonia from L-histidine (17), resulting in the formation of urocanoic acid [Scheme 12.6-4, (6)], an intermediate in the metabolism of l-histidine,n). HAL has also been identified as a key enzyme in the synthesis of secondary metabolites such as Nikkomycin in Streptomyces tendae,ul The mechanism of the enzyme has been investigated and seems to proceed via the carbanion intermediate111, 13]. Synthetic applications of HAL are difficult to achieve, particularly as the enzyme is sensitive to oxygen1131. The utility of HAL is limited to niche applications such as the synthesis of radiolabeled urocanic acids as tracers of histidine metabolism1"1. 

Biochemical Mechanisms of Phenylalanine and Tyrosine Ammonia Lyases Comparison to Histidine Ammonia Lyases... 

Our earlier comprehensive review had summarized both the discovery and purification of PAL (TAL), as well as the central reliance of these pioneering studies in comparison with that of the related histidine ammonia lyase (HAL, EC 4.3.1.3). PAL and TAL, the most extensively studied enzymatic conversions in plant secondary metabolism, catalyze reversible eliminations of ammonium ion from Phe (1) and Tyr (2) to yield -cinnamic... 

On the basis of the results of site-directed mutagenesis and X-ray crystallographic studies, it was proposed that the mechanism of MIO biosynthesis in histidine ammonia-lyase occurs through a self-processing mechanism, with modification of a consecutive sequence of three amino acid residues of the order alanine, serine, and... 

Figure 2 Structure of the MIO cofactor in histidine ammonia lyase from Ps. putida. In this enzyme modification of Aia142, Serf 43, and Gly144 yields the MIO cofactor, which is displayed as sticks colored gray for carbon, red for oxygen, and blue for nitrogen. The coordinates from PDB entry 1b8f were used to display this structure.

Histidine ammonia-lyase is the first enzyme in the degradation pathway of L-histidine and catalyzes the nonoxidative deamination of histidine (12) to form w r-urocanic acid (13) plus ammonia (Equation (3)). Histidine ammonia-lyase is present in several bacteria and in animals. The mechanism for the reaction that is catalyzed by histidine ammonia-lyase is presumed to be similar to that described above for phenylalanine ammonia-lyase (see Scheme 3). 

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