Comparative Studies of Human Recombinant 74- and 54-kDa L-Histidine Decarboxylases

Yatsunami, Kimio; Tsuchikawa, M.; Kamada, Masafumi; Hori, Kouichirou; Higuchi, Takahide

doi:10.1074/jbc.270.51.30813

Cited by 35 publications

(32 citation statements)

References 25 publications

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“…Although we previously showed that in vitro cleavage by elastase of the 74-kDa form, which exhibited a low enzyme activity, resulted in generation of an active 53-kDa form (16), it remains to be clarified whether enzymatical activation occurs upon post-translational processing of HDC in histamine-forming cells. In expression systems, mouse and rat 74-kDa form of HDC were found to exhibit no or little enzyme activity, although enzyme activity of human 74-kDa form was reported to be equivalent to that of the 54-kDa C-terminal deletion mutant (15,18,32). Our results strongly indicate that the proteolytic conversion itself plays a critical role in enzymatic activation of HDC, at least in the mouse mastocytoma cell line.…”

Section: Discussionmentioning

confidence: 61%

Activation of Histidine Decarboxylase through Post-translational Cleavage by Caspase-9 in a Mouse Mastocytoma P-815

Furuta

Nakayama

Sugimoto

et al. 2007

Journal of Biological Chemistry

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L-Histidine decarboxylase (HDC) is the rate-limiting enzyme for histamine synthesis in mammals. Although accumulating evidence has indicated the post-translational processing of HDC, it remains unknown what kinds of proteases are involved. We investigated the processing of HDC in a mouse mastocytoma, P-815, using a lentiviral expression system. HDC was expressed as a 74-kDa precursor form, which is cleaved to yield the 55-and 60-kDa forms upon treatment with butyrate. Alanine-scanning mutations revealed that two tandem aspartate residues (Asp 517 -Asp 518 , Asp 550 -Asp 551 ) are critical for the processing. Treatment with butyrate caused an increase in the enzyme activity of the cells expressing the wild type HDC, but not in the cells expressing the processing-incompetent mutant. An increase in histamine synthesis by butyrate was accompanied by formation of the 55-and 60-kDa form of HDC. In addition, the in vitro translated 74-kDa form of HDC was found to undergo a limited cleavage by purified human caspase-9, whereas the alanine-substituted mutants were not. Processing and enzymatic activation of HDC in P-815 cells was enhanced in the presence of a Zn 2؉ chelator, TPEN. Although treatment with butyrate and TPEN drastically augmented the protease activity of caspase-3, and -9, no apoptotic cell death was observed. Both enzymatic activation and processing of HDC were completely suppressed by a pan-caspase inhibitor, partially but significantly by a specific inhibitor for caspase-9, but not by a caspase-3 inhibitor. These results suggest that, in P-815 cells, histamine synthesis is augmented through the post-translational cleavage of HDC, which is mediated by caspase-9.Histamine plays diverse roles in physiological and pathological responses, such as inflammation, gastric acid secretion, neurotransmission, and immune modulation, by acting on its specific membrane receptors, H 1 , H 2 , H 3 , and H 4 (1-7). L-Histidine decarboxylase (HDC, 2 EC 4.1.1.22) is the rate-limiting enzyme for histamine synthesis in mammals, and targeted disruption of mouse HDC gene resulted in the complete loss of de novo synthesis of histamine (8). Several groups purified HDC from various sources including a mouse mastocytoma, P-815, indicating that purified HDC is a homodimer consisting of a 53-55-kDa subunit (9 -11). In 1990, Joseph et al. (12) succeeded in cDNA cloning of rat HDC for the first time, and demonstrated that the HDC cDNA encodes a protein, of which the molecular mass is 74 kDa. Subsequent cDNA cloning from P-815 cells revealed that mouse HDC cDNA also encodes a 74-kDa protein (13). These results indicate that HDC is initially translated as a 74-kDa form and then converted into the 53-55-kDa form through the post-translational processing. HDC belongs in the fold type I pyridoxal phosphate-dependent enzyme (13,14). Although the region around the active lysine residue of HDC shows homology with the other enzymes in this group, such as the aromatic L-amino acid decarboxylase and glutamate decarboxylase, the C-terminal 20-kDa ...

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Section: Discussionmentioning

confidence: 61%

Activation of Histidine Decarboxylase through Post-translational Cleavage by Caspase-9 in a Mouse Mastocytoma P-815

Furuta

Nakayama

Sugimoto

et al. 2007

Journal of Biological Chemistry

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“…Finally, the primary translation product generated by the pEP-HDC1.5 vector lacks a total of 170 amino acids from the carboxy terminus of the primary HDC sequence. This construct is similar in design and size to constructs which have been used in previous studies (8,47,48), where it was assumed that HDC cleavage involves only carboxy-terminal processing. It was predicted to generate a primary translation product of 54 kDa (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Recombinant experiments showed that a 54-kDa carboxy-terminally truncated HDC isoform had much greater activity than the primary translation product, leading to the general belief that such a regulated step in vivo would facilitate the production of an enzymatically active homodimer of 100 to 110 kDa (8,42,46,47). However, other groups were unable to confirm that the 54-kDa isoform had a higher specific activity (48), and the presence of other isoforms has to some extent been ignored.…”

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confidence: 99%

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Amino- and Carboxy-Terminal PEST Domains Mediate Gastrin Stabilization of Rat l-Histidine Decarboxylase Isoforms

Fleming

Wang

2000

Molecular and Cellular Biology

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Control of enzymatic function by peptide hormones can occur at a number of different levels and can involve diverse pathways that regulate cleavage, intracellular trafficking, and protein degradation. Gastrin is a peptide hormone that binds to the cholecystokinin B-gastrin receptor and regulates the activity of L-histidine decarboxylase (HDC), the enzyme that produces histamine. Here we show that gastrin can increase the steady-state levels of at least six HDC isoforms without affecting HDC mRNA levels. Pulse-chase experiments indicated that HDC isoforms are rapidly degraded and that gastrin-dependent increases are due to enhanced isoform stability. Deletion analysis identified two PEST domains (PEST1 and PEST2) and an intracellular targeting domain (ER2) which regulate HDC protein expression levels. Experiments with PEST domain fusion proteins demonstrated that PEST1 and PEST2 are strong and portable degradation-promoting elements which are positively regulated by both gastrin stimulation and proteasome inhibition. A chimeric protein containing the PEST domain of ornithine decarboxylase was similarly affected, indicating that gastrin can regulate the stability of other PEST domain-containing proteins and does so independently of antizyme/antizyme inhibitor regulation. At the same time, endoplasmic reticulum localization of a fluorescent chimera containing the ER2 domain of HDC was unaltered by gastrin stimulation. We conclude that gastrin stabilization of HDC isoforms is dependent upon two transferable and sequentially unrelated PEST domains that regulate degradation. These experiments revealed a novel regulatory mechanism by which a peptide hormone such as gastrin can disrupt the degradation function of multiple PEST-domain-containing proteins.

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“…The difference in the molecular mass was explained by post-translational processing that truncates a C-terminal region of ϳ20 kDa. The C-terminal truncated 54-kDa form of human recombinant HDC possessed sufficient catalytic activity to support histamine synthesis (15). Therefore, the C-terminal truncated HDC is considered as an active form.…”

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confidence: 99%

Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase

Kakemoto

Nitta

Ueno

et al. 2012

Journal of Biological Chemistry

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Background: HDC catalyzes the rate-limiting step in histamine biosynthesis. Results: A mutation based on the crystal structure of HDC changed the substrate selectivity from L-histidine to L-DOPA. Conclusion: The molecular basis for substrate specificity and recognition of group II PLP-dependent decarboxylases were clarified. Significance: Knowledge of the HDC tertiary structure now makes it possible to design novel drugs that prevent histamine biosynthesis.

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Comparative Studies of Human Recombinant 74- and 54-kDa L-Histidine Decarboxylases

Cited by 35 publications

References 25 publications

Activation of Histidine Decarboxylase through Post-translational Cleavage by Caspase-9 in a Mouse Mastocytoma P-815

Activation of Histidine Decarboxylase through Post-translational Cleavage by Caspase-9 in a Mouse Mastocytoma P-815

Amino- and Carboxy-Terminal PEST Domains Mediate Gastrin Stabilization of Rat l-Histidine Decarboxylase Isoforms

Structural Study Reveals That Ser-354 Determines Substrate Specificity on Human Histidine Decarboxylase

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