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At least 667 records · Page 37

Aerospace Medicine Talk

The presentation is next Sunday, May 10th. It will be to the Civil Aviation Medical Association, for 2 hours at Disney World in Orlando. It is a high level talk on space medicine, including history, the role of my office, human health risks of space flight, general aspects of space medicine practice, human health risk management (including integrated activities of medical operations and the Human Research Program, and thoughts concerning health risks for long duration exploration class space missions. No proprietary data or material will be used, all is readily available in the public sector. There is also a short (30 min) talk on Monday at the CAMA lunch. There we will describe the Visual Impairment and Intracranial Pressure syndrome, with possible etiologies and plans for research (already selected studies). Again, nothing proprietary will be discussed.

Aerospace Medicine Overview↗

Alssat Development Status and Its Applications in Trade Studies

The development of the Advanced Life Support (ALS) Sizing Analysis Tool (ALSSAT) using Microsoft® Excel was initiated by the Crew and Thermal Systems Division (CTSD) of Johnson Space Center (JSC) in 1997 to support the ALS and Exploration Offices in Environmental Control and Life Support System (ECLSS) design and studies. It aids the user in performing detailed sizing of the ECLSS based on suggested default values or user inputs for different combinations of the ALS regenerative system technologies (Ref. 1, 2). This analysis tool will assist the user in performing ECLSS preliminary design and trade studies as well as system optimization efficiently and economically. Since ALSSAT's latest publication in ICES 2001 (Ref. 1) describing the development of ALSSAT with its Air Revitalization Subsystem (ARS), Water Management Subsystem (WMS), and Biomass Subsystem (Biomass) mass balance sheets, ALSSAT has been expanded to include mass balance and sizing models for the remaining three ALS subsystems, namely, the Solid Waste Management Subsystem (SWMS), the Food Management Subsystem (FMS), and the Thermal Control Subsystem (TCS). The external interfaces, including the Extravehicular Activities (EVA) and Human Accommodations (HA), were implemented into ALSSAT in 2002. The overall mass balance sheet, which integrates the six ALS subsystems and the external interfaces applicable to the ECLSS, was also developed. In 2003, ALSSAT was upgraded to include the consideration of redundancy and contingency options in the ECLSS, as well as more ALS regenerative technology selections. ALSSAT has been used for the Metric Calculation for FY02 and FY03 (Ref. 3). Several trade studies were conducted in 2003. The analytical results will be presented in this paper.

Yeh, H. Y. (Jannivine)↗

A First Look at the Upcoming SISO Space Reference FOM

Spaceflight is difficult, dangerous and expensive; human spaceflight even more so. In order to mitigate some of the danger and expense, professionals in the space domain have relied, and continue to rely, on computer simulation. Simulation is used at every level including concept, design, analysis, construction, testing, training and ultimately flight. As space systems have grown more complex, new simulation technologies have been developed, adopted and applied. Distributed simulation is one those technologies. Distributed simulation provides a base technology for segmenting these complex space systems into smaller, and usually simpler, component systems or subsystems. This segmentation also supports the separation of responsibilities between participating organizations. This segmentation is particularly useful for complex space systems like the International Space Station (ISS), which is composed of many elements from many nations along with visiting vehicles from many nations. This is likely to be the case for future human space exploration activities. Over the years, a number of distributed simulations have been built within the space domain. While many use the High Level Architecture (HLA) to provide the infrastructure for interoperability, HLA without a Federation Object Model (FOM) is insufficient by itself to insure interoperability. As a result, the Simulation Interoperability Standards Organization (SISO) is developing a Space Reference FOM. The Space Reference FOM Product Development Group is composed of members from several countries. They contribute experiences from projects within NASA, ESA and other organizations and represent government, academia and industry. The initial version of the Space Reference FOM is focusing on time and space and will provide the following: (i) a flexible positioning system using reference frames for arbitrary bodies in space, (ii) a naming conventions for well-known reference frames, (iii) definitions of common time scales, (iv) federation agreements for common types of time management with focus on time stepped simulation, and (v) support for physical entities, such as space vehicles and astronauts. The Space Reference FOM is expected to make collaboration politically, contractually and technically easier. It is also expected to make collaboration easier to manage and extend.

Mueller, Bjorn↗

Variable Vector Countermeasure Suit (V2Suit) for Space Habitation and Exploration

The Variable Vector Countermeasure Suit (V2Suit) for Space Habitation and Exploration is a visionary system concept that will revolutionize space missions by providing a platform for integrating sensors and actuators with daily astronaut intravehicular activities to improve human health and performance. The V2Suit uses control moment gyroscopes (CMGs) within a miniaturized module placed on body segments to provide a viscous resistance during movements _ a countermeasure to the sensorimotor and musculoskeletal adaptation performance decrements that manifest themselves while living and working in microgravity and during gravitational transitions during long-duration spaceflight, including post-flight recovery and rehabilitation. Through an integrated design, system initialization, and control systems approach the V2Suit is capable of generating this viscous resistance along an arbitrarily specified direction of down. When movements are made, for example, parallel to that down direction a resistance is applied, and when the movement is perpendicular to that direction no resistance is applied. The V2Suit proposes to be a countermeasure to this spaceflight-related adaptation and de-conditioning and the unique sensorimotor characteristics associated with living and working in 0-G, which are critical for future long-duration space missions. This NIAC Phase II project leveraged the study results from Phase I and focused on detailing several aspects of the V2Suit concept, including a wearable CMG architecture, control steering laws, human-system integration evaluations, developing a brassboard prototype unit as a proof-of-concept, as well as evaluating the concept in the context of future space exploration missions. A human mission to Mars, such as that outlined in the Mars Design Reference Architecture 5.0, provides a framework for determining the concept of operations and requirements for the V2Suit system. Mars DRA 5.0 includes approximately 180 day 0-G transits to- and from- Mars, as well as a 500 day stay on the surface (~3/8-G) (Figure 3). Accordingly, there are four gravitational transitions associated with this mission: 1-G to 0-G (Earth launch), 0-G to 3/8-G (Mars landing), 3/8-G to 0-G (Mars launch), and 0-G to 1-G (Earth landing). This reference mission provided the basis for developing high-level operational requirements to guide the subsequent study and design of the key V2Suit components.

Duda, Kevin R.↗

Variable Vector Countermeasure Suit (V2Suit) for Space Habitation and Exploration

The "Variable Vector Countermeasure Suit (V2Suit) for Space Habitation and Exploration" is a visionary system concept that will revolutionize space missions by providing a platform for integrating sensors and actuators with daily astronaut intravehicular activities to improve human health and performance. The V2Suit uses control moment gyroscopes (CMGs) within a miniaturized module placed on body segments to provide a "viscous resistance" during movements and a countermeasure to the sensorimotor and musculoskeletal adaptation performance decrements that manifest themselves while living and working in microgravity and during gravitational transitions during long-duration spaceflight, including post-flight recovery and rehabilitation. Through an integrated design, system initialization, and control systems approach the V2Suit is capable of generating this "viscous resistance" along an arbitrarily specified direction of "down." When movements are made, for example, parallel to that "down" direction a resistance is applied, and when the movement is perpendicular to that direction no resistance is applied. The V2Suit proposes to be a countermeasure to this spaceflight-related adaptation and de-conditioning and the unique sensorimotor characteristics associated with living and working in 0-G, which are critical for future long-duration space missions.This NIAC Phase I project focused on detailing several aspects of the V2Suit concept, including human-system integration, system architecture, computer aided design (CAD) modeling, and closed-loop simulation and analysis. In addition, early-stage breadboard prototyping of several aspects of the V2Suit system modules enabled characterization of expected performance and identified areas for further research and development to enable operational implementation of the V2Suit. In particular, potential challenges with integration of commercial-off-the-shelf components were identified. The key enabler for operational use and adoption of the V2Suit is a low-profile body worn form factor that does not interfere with normal, everyday movements and interfaces adequately with the body as to provide the generated gyroscopic torque for the perceptions of movement with a "viscous resistance." These aspects were investigated through mockups using a life-size mannequin, and through body attachment mechanisms on the breadboard prototype. Through the evaluation and investigation of commercially-available components, as well as an identification of desirable form factors, CAD models of the V2Suit modules were developed. These models included all of the required elements and spin motors, flywheel masses, gimbal motors, slip rings, inertial measurement units, motor controllers, and the required mounting brackets/hardware and cabling. The configuration and orientation of the control moment gyroscopes (CMGs) was specified according to results from the modeling, simulation and analysis. Two revisions of the CAD model were investigated through closed-loop simulation of the CMGs, and their ability to generate a resultant reaction force during movement and null undesirable torques due to changes in the direction of the angular momentum vector as a result of the normal body movements.

space missions↗

Recommended Crew Systems Capabilities for a 30 to 90 Day Four-Crew Lunar Surface Mission

For any given surface mission duration, there exists a set of surface capabilities necessary to sustain a four-person crew for the length of time the crew is on the surface. Identifying these capabilities is important to mission planners and spacecraft design engineers responsible for lunar surface habitation elements, who need to know which systems and capabilities must be prioritized for the vehicles they are designing. However, simply identifying the surface capabilities does not necessarily equal a viable surface configuration. These capabilities may or may not satisfy stakeholder expectations or even permit completion of mission objectives. Lunar lander cargo mass constraints are a powerful forcing function that requires significant efforts to reduce the mass of all surface elements, including those supporting crew habitation. The required capabilities do increase as a function of mission duration, but it is a nonlinear growth. There are key points in mission duration, beyond which certain additional capabilities are needed. This forms bands of capability between each point. Within a given band, the same functional capabilities are needed, and the only scaling is that associated with daily consumables. The next higher band requires additional capabilities. This paper will focus on those capabilities needed for missions of 30-90 days. It should be noted that there are some uncertainties interpreting NASA requirements that require capabilities after a certain number of days, as typically this refers to number of days in space, not number of days on the lunar surface. Depending on transportation architecture, the number of days between Earth launch and lunar surface landing may vary, therefore impacting when certain required capabilities are implemented. However, activities to prepare humans for missions to Mars and commercial interest in lunar development may drive progressive increases in surface duration. Missions up to 30 days are expected to follow the initial 6.5-day surface missions and there may be commercial interest in extending to even greater durations. This paper will examine the potential case of a 30-90-day surface mission duration with respect to the systems necessary to support crew living and working on the lunar surface.

Habitat↗

Impacts of Degradation on Water, Energy, and Carbon Cycling of the Amazon Tropical Forests

Selective logging, fragmentation, and understory fires directly degrade forest structure and composition. However, studies addressing the effects of forest degradation on carbon, water, and energy cycles are scarce. Here, we integrate field observations and high‐resolution remote sensing from airborne lidar to provide realistic initial conditions to the Ecosystem Demography Model (ED‐2.2) and investigate how disturbances from forest degradation affect gross primary production (GPP), evapotranspiration (ET), and sensible heat flux (H). We used forest structural information retrieved from airborne lidar samples (13,500 ha) and calibrated with 817 inventory plots (0.25 ha) across precipitation and degradation gradients in the eastern Amazon as initial conditions to ED‐2.2 model. Our results show that the magnitude and seasonality of fluxes were modulated by changes in forest structure caused by degradation. During the dry season and under typical conditions, severely degraded forests (biomass loss ≥66%) experienced water stress with declines in ET (up to 34%) and GPP (up to 35%) and increases of H (up to 43%) and daily mean ground temperatures (up to 6.5°C) relative to intact forests. In contrast, the relative impact of forest degradation on energy, water, and carbon cycles markedly diminishes under extreme, multiyear droughts, as a consequence of severe stress experienced by intact forests. Our results highlight that the water and energy cycles in the Amazon are driven by not only climate and deforestation but also the past disturbance and changes of forest structure from degradation, suggesting a much broader influence of human land use activities on the tropical ecosystems.

Marcos Longo↗

Climate and Human Impacts on Hydrological Processes and Flood Risk in Southern Louisiana

Satellite observations of coastal Louisiana indicate an overall land loss over recent decades, which could be attributed to climate and human-induced factors, including sea level rise (SLR). Climate induced hydrological change (CHC) has impacted the way flood control structures are used, altering the spatiotemporal water distribution. Based on “what-if” scenarios, we determine relative impacts of SLR and CHC on increased flood risk over southern Louisiana and examine the role of water management, via flood control structures, in mitigating flood risk over the region. Our findings show that CHC has increased flood risk over the past 28 years. The number of affected people increases as extreme hydrological events become more exceptional. Water management reduces flood risk to urban areas and croplands, especially during exceptional hydrological events. For example, currently (i.e., 2016-2020 period), CHC-induced flooding puts an additional 73km2 of cropland under flood risk at least half of the time (median flood event) and 65km2 once a year (annual flood event), when compared to a past period (1993-1997). A ten- to twenty-fold increase relative to SLR-induced flooding. CHC also increases population vulnerability in southern Louisiana to flooding; additional 9900 residents currently live under flood risk at least half of the time, and that number increases to 27,400 for annual flood events. Residents vulnerable to SLR induced flooding is lower (6000 and 3300 residents, respectively). Conclusions are that CHC is a major factor that should be accounted for flood resilience and that water management interventions can mitigate risks to human life and activities.

Augusto Getirana↗

Advancements in Frequency Domain Analysis of Dual Centerline Propellant Tanks for Space Vehicle Stability and Design

This paper presents advancements in the frequency domain stability analysis for landing and ascent vehicle configurations with dual centerline propellant tanks, developed in support of Guidance, Navigation, and Control (GNC) insight activities for the Human Landing System project. The study focuses on the impact of axial thrust on the dual tank slosh danger zone solution. The frequency domain stability analysis tool is developed within the GeneraLized Aerospace Simulation in Simulink® (GLASS) framework at NASA Marshall Space Flight Center. The frequency domain stability analysis tool is used to determine slosh damping and control systems design requirements. The accuracy of the tool’s instability predictions is validated against time-domain outcomes within the GLASS simulation environment, showing consistent and anticipated results. Additionally, the method is validated by comparing its results with Frequency Domain Analysis and Comparison Tool Assuming Linearity (FRACTAL), a frequency domain analysis tool with extensive heritage and rigorous verification and validation using NASA Ares I-X and SLS flight data. The findings of this paper contribute to a better understanding of dual-tank slosh instability and support improved design and operation margins of space vehicles.

Han Woong (Brian) Bae↗

Advancements in Frequency Domain Analysis of Dual Centerline Propellant Tanks for Space Vehicle Stability and Design

This paper presents advancements in the frequency domain stability analysis for landing and ascent vehicle configurations with dual centerline propellant tanks, developed in support of Guidance, Navigation, and Control (GNC) insight activities for the Human Landing System project. The study focuses on the impact of axial thrust on the dual tank slosh danger zone solution. The frequency domain stability analysis tool is developed within the GeneraLized Aerospace Simulation in Simulink® (GLASS) framework at NASA Marshall Space Flight Center. The frequency domain stability analysis tool is used to determine slosh damping and control systems design requirements. The accuracy of the tool’s instability predictions is validated against time-domain outcomes within the GLASS simulation environment, showing consistent and anticipated results. Additionally, the method is validated by comparing its results with Frequency Domain Analysis and Comparison Tool Assuming Linearity (FRACTAL), a frequency domain analysis tool with extensive heritage and rigorous verification and validation using NASA Ares I-X and SLS flight data. The findings of this paper contribute to a better understanding of dual-tank slosh instability and support improved design and operation margins of space vehicles.

Han Woong (Brian) Bae↗

An overview of Japanese CELSS research activities

Development of Controlled Ecological Life Support System (CELSS) technology is inevitable for future long duration stays of human beings in space, for lunar base construction and for manned Mars flight programs. CELSS functions can be divided into 2 categories, Environmental Control and Material Recycling. Temperature, humidity, total atmospheric pressure and partial pressure of oxygen and carbon dioxide, necessary for all living things, are to be controlled by the environment control function. This function can be performed by technologies already developed and used as the Environment Control Life Support System (ECLSS) of Space Shuttle and Space Station. As for material recycling, matured technologies have not yet been established for fully satisfying the specific metabolic requirements of each living thing including human beings. Therefore, research activities for establishing CELSS technology should be focused on material recycling technologies using biological systems such as plants and animals and physico-chemical systems, for example, a gas recycling system, a water purifying and recycling system and a waste management system. Japanese research activities were conducted and will be continued accordingly.

Nitta, Keiji↗

Absence of arterial baroreflex modulation of skin sympathetic activity and sweat rate during whole-body heating in humans

1. Prior findings suggest that baroreflexes are capable of modulating skin blood flow, but the effects of baroreceptor loading/unloading on sweating are less clear. Therefore, this project tested the hypothesis that pharmacologically induced alterations in arterial blood pressure in heated humans would lead to baroreflex-mediated changes in both skin sympathetic nerve activity (SSNA) and sweat rate. 2. In seven subjects mean arterial blood pressure was lowered (approximately 8 mmHg) and then raised (approximately 13 mmHg) by bolus injections of sodium nitroprusside and phenylephrine, respectively. Moreover, in a separate protocol, arterial blood pressure was reduced via steady-state administration of sodium nitroprusside. In both normothermia and heat-stress conditions the following responses were monitored: sublingual and mean skin temperatures, heart rate, beat-by-beat blood pressure, skin blood flow (laser-Doppler flowmetry), local sweat rate and SSNA (microneurography from peroneal nerve). 3. Whole-body heating increased skin and sublingual temperatures, heart rate, cutaneous blood flow, sweat rate and SSNA, but did not change arterial blood pressure. Heart rate was significantly elevated (from 74 +/- 3 to 92 +/- 4 beats x min(-1); P < 0.001) during bolus sodium nitroprusside-induced reductions in blood pressure, and significantly reduced (from 92 +/- 4 to 68 +/- 4 beats x min(-1); P < 0.001) during bolus phenylephrine-induced elevations in blood pressure, thereby demonstrating normal baroreflex function in these subjects. 4. Neither SSNA nor sweat rate was altered by rapid (bolus infusion) or sustained (steady-state infusion) changes in blood pressure regardless of the thermal condition. 5. These data suggest that SSNA and sweat rate are not modulated by arterial baroreflexes in normothermic or moderately heated individuals.

Clinical Trial↗

Considerations for Health and Performance During Surface Extravehicular Activities

BACKGROUND: NASA’s objectives for expanding human presence beyond low Earth orbit will require Extravehicular Activities (EVAs) on lunar and planetary surfaces. Given the physiological and functional demands of conducting surface EVAs in a pressurized spacesuit in reduced gravity environments, there is a possibility that crew injury and compromised physiological and/or functional performance may present. OVERVIEW: Many human health and performance knowledge gaps exist in regards to exploration EVA that require characterization to ensure safety, reliability, and mission success. To address knowledge gaps, EVA simulations in Earth-based analog environments and/or spacesuit simulators can be utilized to provide valuable insights into task-based physiologic and metabolic costs, cognitive loads, and associated operational limitations to inform future mission concepts. Physical workloads approaching 60% of maximum metabolic rates and 85% age-predicted heart rate maxima; core body temperatures approaching 100o F; and subjective responses indicating limited spare cognitive capacity via Bedford scale have been observed during ground-based exploration EVA simulations in the NASA Active Response Gravity Offload Simulator (ARGOS) and Neutral Buoyancy Lab (NBL) during simulated planetary EVAs in pressurized suits. Further, ground-based EVA analogs vary in their ability to simulate planetary EVA and resulting physical workloads. DISCUSSION: Metabolic costs, thermal burdens, functional strength, and cognitive impacts have been and must continue to be assessed in ground-based analogs to fully characterize operational demands and crew readiness levels for exploration EVA. Considerations should be given to enabling a new concept of high-tempo surface EVA operations and associated work-rest intervals, understanding human health and performance impacts of evolving commercial suit designs and capabilities, and predictive modeling and decision support capabilities to enable safe and successful EVA operations.

EVA↗

Considerations for Health and Performance during Surface Extravehicular Activities

BACKGROUND: NASA’s objectives for expanding human presence beyond low Earth orbit will require Extravehicular Activities (EVAs) on lunar and planetary surfaces. Given the physiological and functional demands of conducting surface EVAs in a pressurized spacesuit in reduced gravity environments, there is a possibility that crew injury and compromised physiological and/or functional performance may present. OVERVIEW: Many human health and performance knowledge gaps exist in regards to exploration EVA that require characterization to ensure safety, reliability, and mission success. To address knowledge gaps, EVA simulations in Earth-based analog environments and/or spacesuit simulators can be utilized to provide valuable insights into task-based physiologic and metabolic costs, cognitive loads, and associated operational limitations to inform future mission concepts. Physical workloads approaching 60% of maximum metabolic rates and 85% age-predicted heart rate maxima; core body temperatures approaching 100° F; and subjective responses indicating limited spare cognitive capacity via Bedford scale have been observed during ground-based exploration EVA simulations in the NASA Active Response Gravity Offload Simulator (ARGOS) and Neutral Buoyancy Lab (NBL) during simulated planetary EVAs in pressurized suits. Further, ground-based EVA analogs vary in their ability to simulate planetary EVA and resulting physical workloads. DISCUSSION: Metabolic costs, thermal burdens, functional strength, and cognitive impacts have been and must continue to be assessed in ground-based analogs to fully characterize operational demands and crew readiness levels for exploration EVA. Considerations should be given to enabling a new concept of high-tempo surface EVA operations and associated work-rest intervals, understanding human health and performance impacts of evolving commercial suit designs and capabilities, and predictive modeling and decision support capabilities to enable safe and successful EVA operations.

P Estep↗

Induction of ceruloplasmin synthesis by IFN-gamma in human monocytic cells

Ceruloplasmin is a 132-kDa glycoprotein abundant in human plasma. It has multiple in vitro activities, including copper transport, lipid pro- and antioxidant activity, and oxidation of ferrous ion and aromatic amines; however, its physiologic role is uncertain. Although ceruloplasmin is synthesized primarily by the liver in adult humans, production by cells of monocytic origin has been reported. We here show that IFN-gamma is a potent inducer of ceruloplasmin synthesis by monocytic cells. Activation of human monoblastic leukemia U937 cells with IFN-gamma increased the production of ceruloplasmin by at least 20-fold. The identity of the protein was confirmed by plasmin fingerprinting. IFN-gamma also increased ceruloplasmin mRNA. Induction followed a 2- to 4-h lag and was partially blocked by cycloheximide, indicating a requirement for newly synthesized factors. Ceruloplasmin induction in monocytic cells was agonist specific, as IL-1, IL-4, IL-6, IFN-alpha, IFN-beta, TNF-alpha, and LPS were completely ineffective. The induction was also cell type specific, as IFN-gamma did not induce ceruloplasmin synthesis in endothelial or smooth muscle cells. In contrast, IFN-gamma was stimulatory in other monocytic cells, including THP-1 cells and human peripheral blood monocytes, and also in HepG2 cells. Ceruloplasmin secreted by IFN-gamma-stimulated U937 cells had ferroxidase activity and was, in fact, the only secreted protein with this activity. Monocytic cell-derived ceruloplasmin may contribute to defense responses via its ferroxidase activity, which may drive iron homeostasis in a direction unfavorable to invasive organisms.

Non-NASA Center↗

Human factors dimensions in the evolution of increasingly automated control rooms for near-earth satellites

The NASA-Goddard Space Flight Center is responsible for the control and ground support for all of NASA's unmanned near-earth satellites. Traditionally, each satellite had its own dedicated mission operations room. In the mid-seventies, an integration of some of these dedicated facilities was begun with the primary objective to reduce costs. In this connection, the Multi-Satellite Operations Control Center (MSOCC) was designed. MSOCC represents currently a labor intensive operation. Recently, Goddard has become increasingly aware of human factors and human-machine interface issues. A summary is provided of some of the attempts to apply human factors considerations in the design of command and control environments. Current and future activities with respect to human factors and systems design are discussed, giving attention to the allocation of tasks between human and computer, and the interface for the human-computer dialogue.

Mitchell, C. M.↗

Next Generation Life Support (NGLS): High Performance EVA Glove (HPEG) Technology Development Element

The overall objective is to develop advanced gloves for extra vehicular activity (EVA) for future human space exploration missions and generate corresponding standards by which progress may be quantitatively assessed. The glove prototypes that result from the successful completion of this technology development activity will be delivered to NASA's Human Exploration Operations Mission Directorate (HEOMD) and ultimately to be included in an integrated test with the next generation spacesuit currently under development.

Walsh, Sarah↗

Structural Basis for Flip-Flop Action of Thiamin-Dependent Enzymes Revealed by Crystal Structure of Human Pyruvate Dehydrogenase

The biologically active derivative of vitamin B1; thiamin pyrophosphate; is used as cofactor by many enzymes that perform a wide range of catalytic functions in the pathways of energy production. In alpha2beta2-heterotetrameric human pyruvate dehydrogenase, the first catalytic component enzyme of human pyruvate dehydrogenase complex, this cofactor is used to cleave the C(sup alpha)-C(=0) bond of pyruvate followed by reductive acetyl transfer to lipoyl-dihydrolipoamide acetyltransferase, the second catalytic component of the complex. The dynamic nonequivalence of two, otherwise chemically equivalent, catalytic sites have puzzled researchers from earlier functional studies of this enzyme. In order to gain insight into the mechanism of action of this enzyme, we determined the crystal structure of the holoform of human pyruvate dehydrogenase at 1.958, resolution. We propose a kinetic model for the flip-flop action of this enzyme through the concerted approx. 2A, shuttle-like motion of the heterodimers. The similarity of thiamin pyrophosphate binding in human pyruvate dehydrogenase and other functionally related enzymes suggests this newly defined mechanism of shuttle-like motion of domains to be common for the family of thiamin pyrophosphate-dependent enzymes.

Ciszak, Ewa↗